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Background The efficacy of first-line chemoradiotherapy for overall survival (OS) might be confounded by the subsequent treatments in patients with locally advanced non-small cell lung cancer (NSCLC). In this study, we assessed the associations of progression-free survival (PFS) and post-progression survival (PPS) with OS after chemoradiotherapy for locally advanced NSCLC using patient-level data. Patients and methods Between January 2011 and December 2018, 45 patients with locally advanced NSCLC who had received first-line chemoradiotherapy and in whom recurrence occurred were analysed. The associations of PFS and PPS with OS were analysed at the individual level. Results Linear regression and Spearman rank correlation analyses revealed that PPS was strongly correlated with OS (r = 0.72, p < 0.05, R2 = 0.54), whereas PFS was moderately correlated with OS (r = 0.58, p < 0.05, R 2 = 0.34). The Glasgow prognostic score and liver metastases at recurrence were significantly associated with PPS (p < 0.001). Conclusions The current analysis of individual-level data of patients treated with first-line chemoradiotherapy implied that PPS had a higher impact on OS than PFS in patients with locally advanced NSCLC. Additionally, current perceptions indicate that treatment beyond progression after first-line chemoradiotherapy might strongly affect OS.

A 60-year-old man presented with postoperative recurrence of intrahepatic cholangiocarcinoma with right portal vein tumor thrombosis (PVTT). After failure of standard chemotherapy, a liver biopsy showed that his microsatellite instability (MSI) status was high. Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab was commenced, which resulted in a partial response and resolution of the PVTT. There were no significant immune-related adverse events. According to recently published reports, the frequency of MSI-high biliary tract cancer (BTC) is about 0%-2.1%, which is extremely rare. However, ICIs may be effective in patients with MSI-high BTC, such as the present patient.

The purpose of this study was to clarify the opinions of radiation oncologists in Japan regarding treatment for lung cancer complicated with interstitial lung disease (ILD) by a questionnaire survey, and the risk of acute exacerbation (AE) after radiotherapy. Questionnaires were sent to all of the facilities in which radiation therapy is performed for lung cancer in Japan by using the mailing list of the Japanese Society for Radiation Oncology (JASTRO). The questionnaire survey was conducted to clarify who judges the existence of ILD, the indications for radiation therapy in cases of ILD-combined lung cancer, and the ratio of ILD-combined lung cancer in lung cancer patients treated with radiation therapy. Patients with ILD-combined lung cancer who received radiotherapy during the period from April 2014 to March 2015 were retrospectively analysed. Any cases of AE without any other obvious cause were included. ILD confirmation was performed by central radiologists using computed tomography images. A total of 47 facilities responded to the questionnaire. Radiation therapy was an option in cases of ILD-combined lung cancer in 39 (83%) of the facilities. The indication for radiation therapy was based on image findings in 35 (90%) of the 39 facilities in which radiation therapy was acceptable or was a choice in some cases of ILD. The final indication was based on the opinion of the pulmonologist in 29 (74%) of those 39 facilities. In fiscal year 2014, a total of 2128 patients in 38 facilities received chest irradiation. Seventy-eight (3.7%) of those 2128 patients had ILD-combined lung cancer. Sixty-seven patients were included in patient analysis. AE occurred in 5 patients (7.5%), and one of those 5 patients (20.0%) died from radiation-induced AE. The median period from radiotherapy to AE was 4 months (range, 2–7 months). The following four independent risk factors for AE were identified in univariate analysis: non-advanced age (

Purpose To compare the efficacy and the incidence of complications of high-dose-rate (HDR) and low-dose-rate (LDR) intraluminal brachytherapy (IBT) boost after external beam radiation therapy in patients with superficial esophageal cancer. Methods and Materials Fifty-four consecutive patients with Stage I thoracic esophageal squamous cell carcinoma who were treated with definitive radiotherapy using IBT between 1991 and 2007 were studied retrospectively. LDR-IBT and HDR-IBT were performed for 19 and 35 patients, respectively. After external beam radiation therapy of 56–60 Gy with a conventional fractionation, LDR-IBT (5 Gy × 2) or HDR-IBT (3 Gy × 3) was given within 2 weeks. The median follow-up was 47 months (7–151 months). Results Overall, the 5-year overall survival, cause-specific survival (CSS), and locoregional control (LRC) rates were 61%, 86%, and 79%, respectively. The 5-year overall survival, CCS, and LRC rates did not differ significantly between the LDR-IBT and HDR-IBT groups (68% vs. 58% (p = 0.50), 83% vs. 85% (p = 0.63), and 84% vs. 75% (p = 0.42), respectively). Salvage treatment was given in 8 locally recurrent patients, and 6 patients were rescued. The Grade ≥2 late morbidities of esophagus and heart/lung were observed in 5 patients (4 in the LDR-IBT group and 1 in the HDR-IBT group) and 2 patients (one from each group), respectively. Conclusions In view of the safety profile and effectiveness, our results encourage the continued adoption of HDR-IBT as radiation boost in medically inoperable or elderly superficial esophageal cancer patients undergoing definitive radiotherapy.

Despite the wide use of definitive chemoradiotherapy (CRT) for locally advanced esophageal adenocarcinoma, there is little evidence that CRT improves the survival of patients with esophageal adenocarcinoma compared with radiotherapy (RT) alone. Therefore, we retrospectively evaluated the outcome of patients with esophageal adenocarcinoma treated by CRT and RT alone. Patients were treated at the Gunma Prefectural Cancer Center (Ota, Japan) and the Gunma University Hospital (Maebashi, Japan). Patients provided written informed consent before treatment. Patients with distant metastases were excluded. CRT consisting of RT, nedaplatin, and 5-fluorouracil has been performed since 2002 when patients have adequate bone marrow, liver, and renal function. Between November 1993 and April 2006, 8 patients were treated by CRT and 12 were RT alone. The median follow-up period of surviving patients was 19 months. CRT group had a significantly higher complete response rate than those RT alone group (87% vs. 33%, P = 0.05). Of all patients, 2-year overall survival rate was 41% and the median survival time was 18 months. The 2-year overall survival of patients treated by CRT was 58%, significantly better than 24% of those with RT alone (P = 0.02). CRT can improve outcomes of patients with esophageal adenocarcinoma compared with RT alone.

Purpose To assess the efficacy of radiation therapy (RT) by using intraluminal brachytherapy (IBT) combined with external beam RT (EBRT) for submucosal esophageal cancer. Methods and Materials Between 1991 and 2005, 59 consecutive patients received definitive RT without chemotherapy. IBT was performed after patients completed EBRT as a booster therapy for 17 patients, using low-dose-rate Cs-137 sources until 1997, and for 19 patients, using high-dose-rate Ir-192 sources thereafter. The long-term outcomes were investigated with a median follow-up time of 61 months. Results Logoregional recurrences and distant metastases were observed in 14 patients and in 2 patients in the lung, respectively, and 5 patients were rescued by salvage treatments. The 5-year logoregional control and cause-specific survival rates were 75% and 76%, respectively. The 5-year cause-specific survival rate in the EBRT group was 62%, whereas the corresponding rate in the IBT group was 86% ( p = 0.04). Multivariate analysis revealed that IBT was the most powerful predictor of survival but did not reach a significant level ( p = 0.07). There were five esophageal ulcers in the IBT group, but no ulcers developed with small fractions of 3 Gy. Grade 2 or higher cardiorespiratory complications developed in 2 patients (5.6%) in the IBT group and in 3 patients (13.0%) in the EBRT group. Conclusions Combining IBT with EBRT is suggested to be one of the preferable treatment modalities for medically inoperable submucosal esophageal cancer because of its preferable local control and survival probabilities, with appreciably less morbidity.

Background and Aim: The aim of this study was to clarify the efficacy and limitations of radiation therapy (RT) for superficial esophageal carcinoma, and to explore the indications for more aggressive therapy, such as combined chemo-radiotherapy. Methods: Sixty-eight patients with stage I (UICC T1N0M0) esophageal squamous cell carcinoma treated by definitive RT alone were analyzed. Brachytherapy was administered in 36 patients as a boost, and the prescribed doses were 10 Gy (5 Gy × 2 times) at a low dose rate (19 patients) and 9 Gy (3 Gy × 3 times) at a high dose rate (17 patients). Recurrence patterns and survival rates were assessed and the factors predisposing to recurrences after RT were statistically investigated by univariate analysis. Results: The 5-year cause-specific survival rate and the locoregional control rate were 79.9% and 82.1%, respectively. No case of recurrence or disease-related death was observed in any of the patients with mucosal cancer. Among the cases with the cancer invading the submucosa, there were 12 cases with locoregional recurrence and two cases with distant metastases. In cases of submucosal esophageal cancer, the tumor length was the only statistically significant factor predicting locoregional control. The 5-year locoregional control rate in cases with a short length of the tumor (≤5 cm) was 83.3%, whereas the corresponding rate in cases with the tumor measuring >5 cm in length was 57.8% (P = 0.036). Patients treated by additional brachytherapy exhibited better cause-specific survival and locoregional control rates than those receiving external RT alone, however, the addition had no statistically significant influence on the outcome. Conclusions: RT was a successful treatment for stage I esophageal cancer, and the treatment outcome using RT was nearly comparable to that of surgery. However, it is suggested that chemo-radiation should be considered in inoperable cases of submucosal cancer when the tumor is more than 5 cm in length.

Purpose: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. Methods and Materials: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for ≥12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy × 5 in 13 patients; 7 Gy × 3 in 19 patients; and 9 Gy × 2 in 68 patients. Results: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. Conclusions: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.

Purpose: The impact of concurrent chemotherapy on the local control in patients with T2N0 laryngeal cancer who receive radiation therapy (RT) was evaluated. Methods and Materials: Sixty-three patients with T2N0 laryngeal cancer who were treated by definitive RT were analyzed. The primary site of the cancer was the glottis in 50 patients, the supraglottis in 9 patients, and the subglottis in 4 patients. Thirty-six patients were treated by RT alone and the remaining 27 patients received concurrent chemoradiotherapy (CRT). Results: Complete response (CR) was obtained in 92% of the patients who received RT alone and 100% of the patients who received CRT. Voice preservation in the group who received CRT (89%) was significantly higher than that in the group treated by RT alone (61%). The 5-year disease-free survival rates in those who received concurrent CRT was significantly superior to that in the patients who received RT alone, although no significant difference was seen in the cause-specific survival rate between the 2 groups. The multivariate analysis revealed that the treatment method (RT alone vs. CRT) was the most significant risk factor that predicted recurrence after RT. Conclusion: Concurrent CRT had a positive impact on the local control of T2N0 laryngeal cancer.

Goals and background There are great differences between treatment methods for early-stage esophageal cancer in institutions. Radiation therapy has been considered to be an effective modality as organ-preserving treatment of the disease. The aim of this study is to assess the effect and limitation of radiation therapy on patients with early esophageal cancer. Study The subjects were 38 patients with stage I (T1N0M0) squamous cell carcinoma of the esophagus who had received definitive radiation therapy alone. Eleven tumors were assessed within the mucosal layer, whereas 27 tumors showed submucosal invasion by examination using endoscopic ultrasound. All patients were treated with more than 60 Gy using a conventional daily fractionation dose at 2 Gy. An additional boost with brachytherapy was performed for 20 patients, and the prescribed doses were 10 Gy (5 Gy x 2 times) with low dose rate (8 patients) and 9 Gy (3 Gy x 3 times) with high dose rate (12 patients). Outcomes and prognostic factors, including the efficacy of intraluminal brachytherapy, were investigated. Results The cause-specific survival rate and the local control rate at 5 years were 82.6% and 86.3%, respectively. Recurrences were noted in 8 patients with submucosal cancer, but no recurrence was observed in patients with mucosal cancer. In the present study, tumor length was a statistically significant prognostic factor for cause-specific survival (P = 0.018) and tumor depth tended toward statistical significance (P = 0.073). In 27 patients with submucosal cancer, the tumor length was also statistically significant for the survival (P = 0.032). The 5-year cause-specific survival rates for the short tumor group and the long tumor group were 85.7% and 55.6%, respectively. On the other hand, the use of intraluminal brachytherapy had no significant effect on patient survival. Conclusion Radiation therapy is very effective for early esophageal squamous cell carcinoma with tumor length less than 5 cm, but other treatment modalities, including chemoradiotherapy especially for inoperable patients, should be considered for submucosal cancer with a tumor length of 5 cm or more.

Purpose The aim of the study is to develop high-dose-rate (HDR) conformal interstitial brachytherapy by means of combined CT-fluoroscopy guidance with CT-based treatment planning for locally recurrent rectal carcinoma. Methods and materials Brachytherapy needle insertion was guided with a helical CT scanner providing continuous fluoroscopy reconstruction. A video monitor placed adjacent to the CT gantry simultaneously allowed the operator to see the process of needle insertion. Final CT images were transferred by an online system to the treatment-planning computer, which reconstructed the implant needles and organ contours. The doses in planning target volume were normalized and geometrically optimized. The patients received a brachytherapy dose at 5 Gy twice daily with a hypofractionated accelerated schedule at a total dose of 30–50 Gy with or without external radiation therapy. Eighteen patients were treated with this procedure. Results Ten to thirty-six needles (average, 17.3) were successfully placed to the planning target volume in each patient. The average time for CT fluoroscopy was 357 seconds for each procedure. No accident was seen at needle insertion, but 2 patients developed incomplete peroneal nerve palsy after needle removal, but gradually recovered. CT-based treatment planning was faster and more accurate than projection reconstruction with conventional radiograms. Analysis of the dose volume histogram showed conformal dose distribution to the target, while avoiding normal structures. Conclusion CT fluoroscopy guidance ensures safety and increases the accuracy of needle placement in brachytherapy. Conformal high-dose-rate (HDR) interstitial brachytherapy with CT-based treatment planning is a method worth considering for locally recurrent rectal cancer.

To analyze the results of radiotherapy (RT) for malignant lymphoma of the orbit and to evaluate them compared with the World Health Organization (WHO) classification published in 2001.The data from 29 patients with malignant lymphoma of the orbit treated with RT at Gunma University Hospital between 1978 and 2001 were retrospectively analyzed. Pathologic slides from 23 cases were available and were reviewed by a hematopathologist according to the WHO classification. The original and reviewed diagnoses, patient characteristics, treatment results, and complications were analyzed. In principle, patients with low-grade or indolent lymphoma were treated with RT alone, using 30 Gy as the tumor dose. Survival data were calculated using the Kaplan-Meier method.One case that proved to be a pseudotumor was excluded from evaluation. Of the 28 cases, 25 were Stage IAE, 1 was Stage IIAE, and 2 were Stage IVAE. The median follow-up was 71 months. According to the original classification and the Working Formulation, the 5- and 10-year overall survival rate of patients with low-grade lymphoma was 94% and 73%, respectively. The corresponding rates for those with intermediate-grade lymphoma were 67% and 67% (p = 0.15). In contrast, the WHO classification showed a significant difference in the survival curves. The 5- and 10-year overall survival rate of patients with mucosa-associated lymphoid tissue (MALT) lymphoma was 100% and 88%, respectively; for diffuse large B-cell patients, the rates were both 0% (p0.001). In patients with MALT lymphoma, one local and four distant relapses developed; two of them10 years after initial treatment. All of the relapsed MALT lymphomas were controlled by salvage therapy.Excellent local control and survival can be achieved for patients with orbital MALT lymphoma using RT alone. A precise histopathologic diagnosis using the WHO classification and long-term follow-up for10 years is recommended.

It has been demonstrated that hyperthermia can enhance the cytotoxicity of several anticancer drugs. Pirarubicin (THP-adriamycin) is a less cardiotoxic derivative of adriamycin. The thermal enhancement of cytotoxicity of pirarubicin was studied at various elevated temperatures in vitro by using a Chinese hamster cell line, V79. Cell survival curves were obtained at elevated temperatures for V79 cells treated with heat given alone or in combination with pirarubicin, and D0, the treatment time to reduce cell survival from S to S/e, was obtained for each cell survival curve. The relationship between the logarithm of the D0 and the treatment temperature for cells treated with heat alone was biphasic with a breaking point at 43 degrees C, although that for cells treated with a combination of heat and pirarubicin was exponential with no breaking point. The slope of this relationship for heat alone > 43 degrees C was -0.72 +/- 0.094 h/degree C which was not significantly different from the slope for combined heat and pirarubicin, -0.64 +/- 0.032 h/degree C. The results indicated that the cytotoxicity of pirarubicin was thermally enhanced specifically by mild hyperthermia. Pirarubicin uptake into the V79 cells during hyperthermia was independent of the treatment temperature (37, 42, and 44 degrees C), suggesting that the thermal enhancement of pirarubicin was not due to the increased drug-uptake at elevated temperatures. Based on these results, it is predictable that hyperthermia combined with pirarubicin is more effective below 43 degrees C which is easily achievable clinically.

Skull base metastasis of hepatocellular carcinoma is relatively rare, and especially rare when the chief complaint is involuntary movement of the eyeball. We reported a 60-year-old man whose first symptom was involuntary movement of the left eyeball. A tumor, 4 × 3 × 2 cm3, in the skull base was detected by magnetic resonance imaging and a partial resection was performed. The histological diagnosis was consistent with hepatocellular carcinoma. Tumors were detected in the liver by computed tomography and gallium scintigraphy. Therefore it was diagnosed as bone metastasis of hepatocellular carcinoma. Radiotherapy was directed to the skull base, liver and the other sites of bone metastasis. The symptoms were improved.

Infectious mononucleosis (IM) is an acute lymphoproliferative disorder that typically occurs in young patients and is usually caused by Epstein-Barr virus. We report here, two cases of tonsillar lesion of IM resembling marginal zone B-cell lymphoma mucosa-associated lymphoid tissue (MALT) type. The patients consisted of an 18-year-old Japanese woman and a 36-year-old Japanese man. Both patients presented with tonsillar mass. Histologically, in one case, the tonsil showed diffuse proliferation of medium-sized lymphocytes. The medium-sized lymphocytes had round or slightly indented nuclei with a small solitary nucleoli and abundant clear cytoplasm and somewhat resembled monocytoid B-cells. In the remaining one case, the lymphoid follicles had hyperplastic germinal centers with ill-defined borders surrounded by a sheet-like proliferation of polymorphous infiltration showing a marginal zone distribution pattern. On high-power field, the interfollicular area was diffusely infiltrated by a polymorphous infiltrate of medium-sized lymphocytes with angulated nuclei somewhat resembling centrocyte-like cells, immunoblasts, plasma cells, plasmacytoid cells and histiocytes with or without epithelioid cell feature. However, there were no CD43+ B-cells in either lesion. Moreover, the polytypic nature of the B-cells was demonstrated by immunohistochemistry or polymerase chain reaction. Although MALT type lymphoma rarely affected young adults, notably, a number of cases have been reported in the tonsil. The present two cases indicated that acute IM should be added to the differential diagnosis for MALT type lymphoma in young adults.

Patients with brain metastases of non-small cell lung cancer (NSCLC) have a poor prognosis, so chemotherapy and best-supportive care are typically pursued as initial treatments.A 52-year-old man presented with symptoms of disorientation and disturbed consciousness as a result of multiple brain metastases. A histopathological examination revealed that the primary tumor was a large cell carcinoma located in the left upper lung. Whole brain irradiation (WBI) with a total dose of 50 Gy was immediately started. Since the brain tumors were successfully controlled, irradiation of the primary lung lesion with a total dose of 60 Gy was initiated 6 months after the WBI. Afterward, the patient was clinically free from lung cancer, but other cancers developed in the cecum and appendix and were surgically removed. He survived for more than 8 years after the WBI but eventually died of respiratory insufficiency caused by multiple lung metastases. The autopsy findings indicated that the lung lesions were metastatic adenocarcinomas from the appendiceal cancer, and the patient had remained disease-free from lung cancer.In view of the possibility of long-term survival in patients with stage IV NSCLC and brain metastasis, especially those with only intracranial metastases, careful consideration is be needed in the selection of treatment options.

Japanese randomized trials showed that there was a significant impact on survival from stage I adenocarcinoma (AD) of the lung by adjuvant chemotherapy with uracil-tegaful after complete resection but there was no effect for patients with squamous cell carcinoma (SQ). The purpose of this study was to examine the correlation of tumor histology and clinical outcome of radiation therapy (RT) for stage I non-small-cell lung cancer (NSCLC) and to consider the necessity of adjuvant chemotherapy after RT for these patients. The subjects were 83 patients, 54 with SQ and 29 with AD; they had received definitive RT with the total dose ranging from 60 to 80 Gy with conventional fractionation at a daily dose of 2 Gy. The differences between SQ and AD with respect to survival and recurrence pattern were investigated. The 5-year overall survival and cause-specific survival rates were 26.5% and 49.1%, respectively. No difference in survival was observed between SQ and AD patients, and the recurrence rates were almost identical (44% for SQ and 45% for AD). However, the 5-year primary control rate of SQ was significantly poorer than that of AD (SQ: 61.5%; AD: 87.6%; p = 0.03). Conversely, the 5-year metastasis-free survival rate of SQ was significantly better than that of AD (SQ: 88.2%; AD: 53.0%; p = 0.005). The different failure pattern, according to tumor histology, indicates that taking into consideration the difference in their clinical behaviors would also be important for planning RT and surgery for early lung cancer.

To examine the feasibility and efficacy of concurrent weekly docetaxel and radiation therapy as a definitive treatment for head and neck cancer (HNC).Thirty-two patients with primary HNC, who were treated with concurrent weekly docetaxel and radiation therapy, were analysed. The distribution of the disease stage was as follows: Stage II, 18 patients; Stage III, 3 patients; Stage IVA, 7 patients; Stage IVB, 3 patients; the patient of cervical lymph node metastasis with unknown primary tumor was not assessable. The average total dose of radiotherapy was 67.5 Gy. Docetaxel (10 mg/m(2), intravenously, once a week) was given to all patients up to four cycles, and cisplatin (6 mg/m(2), intravenously, five times a week) was also administered to all patients for up to 3 weeks from the beginning of the radiation therapy.Only in two patients did the radiotherapy need to be temporarily interrupted due to the development of acute mucositis. Grade 3 toxicity was observed in six patients. Grade 4 acute mucositis was seen in one patient. The response rate was 100%, and complete response (CR) was observed in 30 patients (94%). At the time of the analysis, the 2 year local control and relapse-free rates in the 30 patients showing CR were 90 and 76%, respectively.Concurrent weekly docetaxel and radiation therapy did not affect the compliance of the patients for the radiation therapy, indicating that the acute toxicities were within acceptable limits.

Purpose: To evaluate the advantages of anatomy-based inverse optimization (IO) in planning high-dose-rate (HDR) brachytherapy. Methods and Materials: A total of 114 patients who received HDR brachytherapy (9 Gy in two fractions) combined with hypofractionated external beam radiotherapy (EBRT) were analyzed. The dose distributions of HDR brachytherapy were optimized using geometric optimization (GO) in 70 patients and by anatomy-based IO in the remaining 44 patients. The correlation between the dose–volume histogram parameters, including the urethral dose and the incidence of acute genitourinary (GU) toxicity, was evaluated. Results: The averaged values of the percentage of volume receiving 80–150% of the prescribed minimal peripheral dose (V 80 –V 150 ) of the urethra generated by anatomy-based IO were significantly lower than the corresponding values generated by GO. Similarly, the averaged values of the minimal dose received by 5–50% of the target volume (D 5 –D 50 ) obtained using anatomy-based IO were significantly lower than those obtained using GO. Regarding acute toxicity, Grade 2 or worse acute GU toxicity developed in 23% of all patients, but was significantly lower in patients for whom anatomy-based IO (16%) was used than in those for whom GO was used (37%), consistent with the reduced urethral dose ( p Conclusion: The results of this study suggest that anatomy-based IO is superior to GO for dose optimization in HDR brachytherapy for prostate cancer.

To investigate the incidence and severity of rectal bleeding after high-dose hypofractionated radiotherapy (RT) for prostate cancer, and to explore the factors affecting the incidence of Grade 2 or worse rectal bleeding.The data of 52 patients who had been treated by external beam RT for localized prostate cancer between 1999 and 2002 were analyzed. All the patients had received hypofractionated external beam RT to a total dose of 69 Gy in 3-Gy fractions, three fractions weekly. The clinical and dosimetric factors affecting the incidence of Grade 2 or worse late rectal bleeding were analyzed by univariate and multivariate analyses. The effect of the percentage of the whole rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose (V(30), V(50), V(80), and V(90), respectively) on the incidence of rectal bleeding was evaluated.Of the 52 patients, 13 (25%) developed Grade 2 or worse rectal bleeding. One patient who needed laser coagulation and blood transfusion for the treatment of rectal bleeding was classified as having Grade 3 rectal bleeding. The median time to the development of Grade 2 or worse rectal bleeding was 11 months. The results of the univariate analysis revealed that the presence of a history of diabetes mellitus (p0.001), and V(30)/= 60%, V(50)/= 40% (p0.05), V(80)/= 25%, and V(90)/= 15% (p0.001) were statistically significant risk factors for the occurrence of Grade 2 or worse rectal bleeding. The results of the multivariate analysis revealed that a history of diabetes mellitus was the most statistically significant risk factor for the occurrence of rectal bleeding after hypofractionated RT for prostate cancer (p0.05).A history of diabetes mellitus was the most statistically significant risk factor for the occurrence of Grade 2 or worse rectal bleeding after high-dose hypofractionated RT, although dosimetric factors were also closely associated with the risk of rectal bleeding.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is an intrinsic marker of tumor hypoxia. It has been considered that the hypoxic status reduces radiosensitivity, but the role of HIF-1alpha in advanced cervical carcinoma is still unclear. The objective of this study was to clarify the impact of HIF-1alpha, human papillomavirus (HPV), and other molecular factors, such as p53, bax, bcl-2, and their correlations on the outcome of patients with Stage IIIB cervical carcinoma in radiation therapy.We analyzed 38 patients with FIGO Stage IIIB squamous cell carcinoma of the cervix treated with radiation therapy alone. All patients received the combination therapy of external beam irradiation and low-dose-rate intracavity brachytherapy. The tumor expressions of HIF-1alpha, p53, bax, and bcl-2 were examined by immunohistochemical staining of the pretreatment paraffin embedded specimens. HPV infection was also detected by polymerase chain reaction. The effects of these parameters on clinical outcomes were analyzed by univariate analysis.Of 38 patients, high expression of HIF-1alpha, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed positive infection with HPV. There was a significant positive correlation between high HIF-1alpha expression and disease recurrence (p0.05). Furthermore, HIF-1alpha had a significant correlation with the recurrence-free survival rate (p = 0.04). No statistical correlation was noted between high HIF-1alpha expression and the local control rate (p = 0.17), whereas the HIF-1alpha status predicted distant metastasis with strong significance (p = 0.03). Conversely, other factors demonstrated no impact on the clinical outcome.The present results suggest that HIF-1alpha is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.

To analyze the results of clinically node-negative, localized hormone-refractory prostate cancer treated with external beam radiotherapy (EBRT) and to investigate the potential prognostic factors that influenced the therapeutic outcome.Fifty-three patients who had developed localized hormone-refractory prostate cancer were treated with EBRT between 1994 and 2001. According to the 1992 American Joint Committee on Cancer clinical stage, 4 patients had T2 and 49 had T3 at the start of RT, and 14 patients had a Gleason score7, 14 had a Gleason score of 7, and 23 had a Gleason score of 8-10. All patients were treated with EBRT using the unblocked oblique four-field technique, with a total dose of 69 Gy. The fraction dose was 3 Gy three times weekly. The median follow-up after RT was 35 months (range, 8-96 months) and after androgen ablation was 73 months (range, 42-156 months).Of 53 patients, 15 patients subsequently developed clinical relapse, including locoregional and/or distant metastases. The site of first relapse was bone metastasis in 10, lymph nodes in 3, and local failure in 2 patients; 3 patients died of prostate cancer during the analysis period. The 3-year and 5-year cause-specific survival rate was 94% and 87%, respectively, and the 3-year and 5-year clinical relapse-free survival rate was 78% and 56%, respectively. The univariate analysis revealed that a short prostate-specific antigen (PSA) doubling time and high PSA value at the start of RT and a high Gleason score were statistically significant factors for the risk of clinical relapse. Multivariate analysis demonstrated that the PSA value (PSAor=15 vs.or=15 ng/mL) at the start of RT was an independent prognostic factor.EBRT could be a treatment of choice for clinically node-negative, localized, hormone-refractory prostate cancer.

Carcinomas are the most common malignancies of the esophagus. Primary malignant lymphoma involving the esophagus is rare, with only a few cases of mucosa-associated lymphoid tissue (MALT) lymphoma of the esophagus having been reported. We report the case of a 74-year-old man who was diagnosed with an esophageal MALT lymphoma. Generally, MALT lymphomas are indolent and tend to disseminate slowly; however, the behavior of this disease is not known clearly, and a standard treatment has not been established because of its rarity. Although complete response was confirmed with 36-Gy irradiation, careful follow-up is necessary for the patient.

This study was performed to investigate how caffeine modifies the cytotoxic effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to 5 mM had less effect on clonogenic survival. The cell killing effect, due to paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic effect of paclitaxel not only in dose–response but also in time–response curves. Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose-dependent manner. In the cell cycle analysis, caffeine alone caused early G1 accumulation, whereas paclitaxel alone caused an early increase in G2-M and a decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed the effect of paclitaxel on cell cycle distribution, where a dose-dependent early increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle modifying agents, such as caffeine, potentially diminish the cytotoxic activity of paclitaxel, and one should be careful when combining such agents.

Purpose: The purpose of this study is to evaluate the amount of hypoxic fraction in a rodent tumor by means of polarographic oxygen electrode, phosphorus-31 magnetic resonance spectroscopy ( 31 P-MRS), and a newly synthesized hypoxic marker, β-D-iodinated azomycin galactopyranoside (β-D-IAZGP). We also investigated the radiosensitivity for tumors of different weights. Methods and Materials: Murine mammary carcinoma cells, FM3A, were subcutaneously implanted into the back of 5-week-old male C3H/He mice. β-D-IAZGP radiolabeled with 123 I or with 125 I was injected intravenously into tumor-bearing mice, and marker distribution was measured by nuclear medicine procedures. Radiosensitivity of the tumor was measured by the in vivo / in vitro clonogenic assay. Tumor oxygenation status was also measured directly by polarographic oxygen electrodes and indirectly estimated from 31 P-MR spectra. Results: Higher accumulation of 123 I-β-D-IAZGP was observed in the tumors than in normal tissues at 24 h after administration. As to biodistribution of 125 I-β-D-IAZGP, the tumor/blood ratio varied widely, but correlated significantly with tumor weight. Mean oxygen pressure (pO 2 ) values and ratios of nucleoside triphosphate β to inorganic phosphate (β-ATP/Pi) and of phosphocreatine to inorganic phosphate (PCr/Pi) decreased significantly with the increase in tumor volume. As tumor volume increased, the surviving fraction of cells from tumors irradiated in vivo increased significantly. Conclusions: The increase in tumor volume was significantly correlated with a reduction in mean pO 2 , a decrease in the ratios of β-ATP/Pi or PCr/Pi, an increase in uptake of β-D-IAZGP, and an increase in radioresistance. Because the uptake of β-D-IAZGP can be measured noninvasively by nuclear medicine techniques, it could be clinically useful for monitoring hypoxia in human tumors.

Although it has been reported that the risk of second malignancies increases in long-term survivors of small cell lung cancer (SCLC) and late recurrence of SCLC is sometimes experienced, it seems uncommon. We recently experienced a case of redevelopment of SCLC after a long disease-free period. The case was considered to be second primary SCLC more than 10 years after the initial treatment. The necessity for lifelong follow-up in long-term survivors of SCLC is emphasized.

Background We attempted dose escalation of standard-fractionated and accelerated-hyperfractionated radiotherapy combined with concurrent cisplatin and vindesine to improve local control and survival in unresectable non-small cell lung cancer. Methods Twenty-one patients were enrolled between June 1996 and August 1997. There were 19 males and two females and their median age was 65 years (range 45-74 years). Performance status was 0 in 10 cases and 1 in 11 cases. Disease stage was IIIA in three cases and IIIB in 18 cases. The cases were randomized to a standard-fractionated arm (n = 10) or an accelerated-hyperfractionated radiotherapy arm (n = 11) with two or three cycles of concomitant cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8 every 4 weeks in both arms. Dose escalation from 60 Gy/30 fractions/6 weeks to 70 Gy/35 fractions/7 weeks was planned in the standard-fractionated radiotherapy group and from 54 Gy/36 fractions/3.6 weeks to 60 Gy/40 fractions/4 weeks and then 66 Gy/44 fractions/4.4 weeks in the accelerated-hyperfractionated radiotherapy group. Results Grade 3 or 4 hematological toxicities were observed as follows: in the standard-fractionated/accelerated-hyperfractionated radiotherapy group, leukocytopenia 9/10, anemia 2/3 and thrombocytopenia 0/2. Grade 3 non-hematological toxicity consisted of esophagitis 0/3, increased serum total bilirubin 2/0 and hypoxia 0/1. Two patients died of radiation pneumonitis in the standard-fractionated radiotherapy group. Dose-limiting toxicity was observed in four of the 10 and seven of the 11 patients at initial dose level of standard-fractionated radiotherapy, 60 Gy/30 fractions/6 weeks, and of accelerated-hyperfractionated radiotherapy, 54 Gy/36 fractions/3.6 weeks, respectively. Thus, we failed to escalate the dose of radiotherapy in both arms. The overall response rate in the standard-fractionated group and the accelerated-hyperfractionated radiotherapy group was 70 and 73% and the 1-year survival rate was 70 and 64%, respectively. Conclusions We concluded that these schedules of radiotherapy with concurrent cisplatin and vindesine were unacceptable for use in patients with unresectable non-small cell lung cancer. Further modifications of the schedule for radiotherapy and evaluation of combination with new chemotherapy are warranted.

To investigate cell killing by means of low dose-rate irradiation (LDRI) combined with concurrent mild hyperthermia and to determine the effect of low-dose caffeine on this combination treatment.Human lung adenocarcinoma cells, LK87, were treated with LDRI (50 cGy/h) in combination with mild hyperthermia at 41 degrees C and low-dose caffeine (1 mM). Cell survival was estimated by clonogenic assay. Flow-cytometry was performed with PI staining using FACScan. Heat-shock protein (HSP72/73) was measured by the Western blotting method. All treatments were simultaneously performed for up to 48 h (24 Gy).LDRI cytotoxicities were enhanced by hyperthermia at 41 degrees C. D0 calculated from the dose-response curve for LDRI combined with 41 degrees C was 3.46 Gy whereas it was 6.55 Gy for LDRI alone. The survival curve for LDRI +41 degrees C demonstrated no chronic thermotolerance up to 48 h. For LDRI + simultaneous low-dose caffeine, cell killing was also enhanced, where D0 was 3.38 Gy at 37 degrees C. Radiosensitization caused by caffeine was enhanced by combination with simultaneous mild hyperthermia at 41 degrees C, where D0=1.78 Gy. Cell cycle analysis demonstrated remarkable G2 and mild G1 arrest for LDRI alone, but only G1 arrest was observed for LDRI combined with 41 degrees C and for LDRI combined with caffeine. Strong and early G1 arrest was observed in the treatment with LDRI + caffeine at 41 degrees C. The amount of HSP72/73 in the combination of LDRI with caffeine at 41 degrees C was less than that at 41 degrees C alone.LDRI cytotoxicity was enhanced by non-lethal hyperthermia. Low dose caffeine produced further cell killing in the combination of LDRI with mild hyperthermia.

Purpose: Phosphorus-31 magnetic resonance spectra ( 31 P-MRS) were obtained from highly apoptotic murine lymphoma xenografts before and up to 24 hr following graded doses of radiation ranging from 2 to 30 Gy. Radiation-induced apoptosis was also estimated up to 24 hr by scoring apoptotic cells in tumor tissue. Methods and Materials: Highly apoptotic murine lymphoma cells, EL4, were subcutaneously transplanted into C57/BL mice. At 7 days after transplantation, radiation was given to the tumor with a single dose at 3, 10, and 30 Gy. The β-ATP/Pi, PME/Pi, and β-ATP/PME values were calculated from the peak area of each spectrum. Radiation-induced apoptosis was scored with counting apoptotic cells on hematoxylin and eosin stained specimens (%apoptosis). Results: The values of % apoptosis 4, 8, and 24 hr after radiation were 21.8, 19.6, and 4.6% at 3 Gy, 35.1, 25.6, and 14.8% at 10 Gy, 38.4, 38.0, and 30.6% at 30 Gy, respectively (cf. 4.4% in control). There was no correlation between early change in β-ATP/Pi and % apoptosis at 4 hr after radiation when most of the apoptosis occurred. An early decrease in PME/Pi was observed at 4 hr after radiation dose at 30 Gy. For each dose, the values of β-ATP/Pi 24 hr after radiation were inversely related to radiation dose. Conclusion: The increase in β-ATP/Pi observed by 31 P-MRS was linked to the degree of histological recovery from radiation-induced apoptosis.

action of VRL. Flow cytometry exhibited cell cycle arrest at G2/M phase. After PDT there was overexpression of anti-apoptotic gene bcl-2. VRL caused downregulation of bcl-2 by phosphorylation and upregulated proapoptotic Bax circumventing resistance to chemotherapy and photocytotoxicity. Irradiation generated oxidative stress stimuli such as reactive oxygen species where an electron transfer event is the initial step for type-I photoinduced damage and predominantly singlet oxygen where an energy transfer reaction from the photoexcited molecule to molecular oxygen is the initial step of type-II biological damage causing tumoral cell death under a ratio of apoptosis versus necrosis. Singlet oxygen as the major mediator of cytotoxicity in PDT induces c-fos and c-jun and activates p38 which phosphorylates transcription factors such as ATF-2 and Elk-1. Photosensitization mediated oxidative stress downregulated MDR-1, MMP-9 and VEGF while it induced proapoptotic genes c-myc and WAF1/CIP1/p21 causing arrest of cell cycle in tumor cells through inhibition of cdk2, cdk6, cyclin D1 and cyclin E. Stress induced second messenger ceramide of the acidic sphingomyelinase was activated stimulating cell death signals. Porfimer sodium exerts its photoactivity to the proteins and lipids of plasma membranes, ER, nuclei and mitochondria where light activation damages irreversibly membranes and reduces the activity of membrane associated enzymes like succinic dehydrogenase. We detect a drop in mitochondrial potential concurrent with a drop in ATP level reducing cell respiration. Release of cyt-c from mitochondria into the cytosol initiates mitochondria associated apoptotic events in tumor cells. This causes an irreversible loss of mitochondrial membrane potential revealed by TMRM. Caspase assays revealed activation of procaspase-3 activity via complex formation with dATP, Apaf-1 and cleavage of procaspase-9. Caspase-3 induces apoptosis causing cleavage of a number of proteins including DFF, PARP, DNA ladder formation, TUNEL cells and DEVDase activity. PCD was also confirmed with TdT assay and DNA elution assay. The majority of tumor cells were eradicated by PCD according to counting DAP1 stained nuclei and FITC cells by fluorescence microscopy. Furthermore, PCD was evaluated with propidium iodide staining and flow cytometry with annexin-V. Irreversible D2 apoptotic signs were exhibited with TEM & SEM. Exposure of phosphatidylserine on the plasma membrane of apoptotic cells activated their phagocytosis by adjacent tumor cells indicating a bystander killing effect. Cytotoxicity was revealed by MTT and BrdU assays measuring metabolic activity and DNA synthesis of tumor and endothelial cells which inhibited angiogenesis.