Association between radiotherapy-induced alteration of programmed death ligand 1 and survival in patients with uterine cervical cancer undergoing preoperative radiotherapy.

PURPOSE: To evaluate radiotherapy-induced changes in the expression of programmed death ligand 1 (PD-L1), programmed death 1 (PD-1), and human leukocyte antigen class I (HLA-1) in patients with uterine cervical cancer, as well as infiltration of CD8+ and Forkhead box P3+ (FoxP3+) T lymphocytes into tumor tissue and the prognostic value of these parameters. MATERIALS AND METHODS: We performed immunohistochemical analysis of pre-radiotherapy biopsies and corresponding post-radiotherapy resected tissues in 104 uterine cervical cancer patients undergoing preoperative chemoradiotherapy or radiotherapy alone. We scored the expression of various proteins to distinguish positive from negative samples. RESULTS: PD-L1-expressing tumor cells (PD-L1 TC) increased significantly after chemoradiotherapy (p = 0.043). CD8+ T cell infiltration (p = 0.002) and FoxP3+ T cell infiltration (p = 0.003) decreased significantly after chemoradiotherapy. Expression of PD­1, PD-L1-expressing immune cells (PD-L1 IC), and HLA­1 did not change after chemoradiotherapy. In biopsy specimens obtained before chemoradiotherapy or radiotherapy, greater infiltration of CD8+ T cells (p = 0.001) and FoxP3+ T cells (p = 0.003) were significant predictors of better overall survival (OS). In surgical specimens obtained after chemoradiotherapy or radiotherapy, greater infiltration of PD-L1 TC was the only significant predictor of better OS (p < 0.001) and was related to a significantly lower probability of out-of-field recurrence (p = 0.005). CONCLUSION: Chemoradiotherapy induced an immunologic shift that increased PD-L1 TC. Chemoradiotherapy has immunological effects that can influence the results of treatment for uterine cervical cancer.

A phase II study of adaptive two-step intensity-modulated radiation therapy (IMRT) with chemotherapy for loco-regionally advanced nasopharyngeal cancer (JCOG1015).

BACKGROUND: A phase II study of adaptive two-step intensity-modulated radiotherapy (IMRT) with chemotherapy for nasopharyngeal cancer (NPC) (JCOG1015) was conducted to evaluate the efficacy and safety. METHODS: Patients aged 20-75 years with stages II-IVB NPC were enrolled. As adaptive two-step IMRT, computed tomography planning was performed twice before IMRT for the initial plan of 46 Gy/23 fractions and during treatment for the boost plan of 24 Gy/12 fractions with a total dose of 70 Gy. Chemotherapy (cisplatin 80 mg/m2/3-weeks × 3 courses) was administered concurrently with IMRT, followed by adjuvant chemotherapy (cisplatin at 70 mg/m2 with 5-FU 700 at mg/m2 for 5 days/4 weeks × 3 courses). RESULTS: Between 2011 and 2014, 75 patients were enrolled from 12 institutions. The 3-year overall survival (OS) for the 75 patients was 88%, and the upper and lower limits of the 95% CI of 78%-94% were higher than the expected 3-year OS of 75% for the target population adjusted by the actual proportion of stage II:III:IV = 21%:44%:35%. The 3-year progression-free survival (PFS) and loco-regional PFS were 71% [59-80%] and 77% [66-85%], respectively. Although no grade 4-5 late toxicities were observed, 15 patients (20%) developed grade 3 late toxicities. Grade 2 xerostomia was noted in 26%, 12%, and 9% at 1, 2, and 3 years after starting IMRT, respectively. CONCLUSIONS: Adaptive two-step IMRT for NPC demonstrated an excellent 3-year OS with acceptable toxicities. This method may be one treatment option for locally advanced NPC.

Prediction of acute gastrointestinal and genitourinary radiation toxicity in prostate cancer patients using lymphocyte microRNA.

BACKGROUND: To search for novel biomarkers that can predict acute radiation toxicity, we conducted microRNA expression analysis of peripheral blood lymphocytes (PBLs). METHODS: The discovery cohort was 69 patients with localized adenocarcinoma of the prostate who received intensity-modulated radiation therapy between October 2007 and October 2010. The validation cohort was 72 patients treated with low-dose-rate brachytherapy between May 2008 and March 2014. After13 microRNAs were selected by TaqMan® Array analysis in a preliminary experiment, expression of these microRNAs in all samples was analyzed by RT-PCR. RESULTS: In the discovery cohort, the average prostate volume, the rectal volume receiving 70 Gy, and expression of miR-410 and miR-221 were significant risk factors for Grade 1-2 gastrointestinal toxicity. Receiver operating characteristic analysis showed that the area under the curve (AUC) was 0.807. The maximum dose to the urinary bladder, prostate volume, pretreatment urinary function score, and miR-99a and miR-221 expression were risk factors for Grade 2 genitourinary toxicity. The corresponding AUC was 0.796. In the validation cohort, reproducibility of these markers was confirmed for gastrointestinal toxicity, but not for genitourinary toxicity. CONCLUSION: Combining radiation dose parameters with microRNA expression in PBLs may be useful for predicting acute gastrointestinal toxicity of radiation therapy, thus contributing to personalized treatment of prostate cancer.

Expression of Ku70 predicts results of radiotherapy in prostate cancer.

BACKGROUND AND PURPOSE: Therapeutic strategy for prostate cancer is decided according to T stage, Gleason score, and prostate-specific antigen (PSA) level. These clinical factors are not accurate enough to predict individual risk of local failure of prostate cancer after radiotherapy. Parameters involved with radiosensitivity are required to improve the predictive capability for local relapse. PATIENTS AND METHODS: We analyzed 58 patients with localized adenocarcinoma of the prostate between August 2007 and October 2010 treated with 76 Gy of intensity-modulated radiotherapy (IMRT) as a discovery cohort and 42 patients between March 2001 and May 2007 treated with three-dimensional conformal radiotherapy (3D-CRT) as a validation cohort. Immunohistochemical examination for proteins involved in nonhomologous end-joining was performed using biopsy specimens. RESULTS: Ku70 expression was not correlated with various clinical parameters, such as the Gleason score and D'amico risk classification, indicating that Ku70 expression was an independent prognostic factor. The predictive value for PSA relapse was markedly improved after the combination of Gleason score and Ku70 expression, as compared with Gleason score alone. In patients treated with radiotherapy and androgen deprivation therapy (ADT), no relapses were observed in patients with Gleason score ≤7 or low Ku70 expression. In contrast, patients with Gleason score ≥8 and high Ku70 expression had high PSA relapse rates. In the validation cohort, similar results were obtained. CONCLUSION: Treatment with 76 Gy and ADT can be effective for patients with Gleason score ≤7 or low Ku70 expression, but is not enough for patients with Gleason score ≥8 and high Ku70 expression and, thus, require other treatment approaches.

Influence of XRCC4 expression in esophageal cancer cells on the response to radiotherapy.

DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation and is mainly repaired by the non-homologous end joining (NHEJ) repair. Immunohistochemical analysis of proteins involved in NHEJ, such as XRCC4 (X-ray repair cross-complementing protein 4), Ku86 and DNA-PKcs (DNA-dependent protein kinase, catalytic subunits), may be useful for predicting tumor radiosensitivity. We examined 92 patients with esophageal squamous cell carcinoma (ECSS) who were treated by radiotherapy between 1999 and 2008. Immunohistochemical examination of tumor tissue for Ki-67 and DSB-related proteins, including XRCC4, Ku86, and DNA-PKcs, was performed using pretreatment biopsy specimens. Low expression of XRCC4 was detected in 31 of 92 examined samples (33.7 %). The 5-year overall survival (OS) rate was 67.7 % in the low expression group and 31.0 % in the high expression group (P = 0.00). Multivariate analysis confirmed that advanced T-stage (HR 3.24, P = 0.01), radiation dose less than 66 Gy (HR 2.23, P = 0.02), absence of systemic chemotherapy (HR 2.59, P = 0.05), and high expression of XRCC4 (HR 12.0, P = 0.02) were independent prognostic factors for predicting poor OS. Other DSB-related proteins and Ki-67 were not predictive factors. XRCC4 expression might have an influence on results of radiotherapy for patients with ESCC.

Influence of Ku86 and XRCC4 expression in uterine cervical cancer on the response to preoperative radiotherapy.

DNA double-strand breaks (DSB) are severe damages induced by ionizing radiation. Non-homologous end joining (NHEJ) is a major mechanism for repairing DSB. Immunohistochemical analysis of proteins involved in NHEJ, such as Ku86 and XRCC4 (X-ray repair cross-complementing protein 4) may be useful for predicting tumor radiosensitivity. We examined the relationship between expression of DSB-related proteins in biopsy specimens of uterine cervical cancer and the pathological effect of 40 Gy of preoperative radiotherapy. 119 patients with uterine cervical cancer were treated between 2000 and 2011. Pathological effects of preoperative radiotherapy were classified by examining hysterectomy specimens. Patients with complete response (pCR) had a significantly better overall 5-year survival rate than those without pCR (96.3 vs. 76.9 %, P = 0.02). The pCR rate was significantly higher in patients with low Ku86 and XRCC4 expression than in other patients (47.4 vs. 21.3 %, P = 0.04). Logistic regression analysis also demonstrated that low Ku86 and XRCC4 expression was a significant predictor of pCR (P = 0.03). Patients with high Ku86 and XRCC4 expression had a significantly lower 5-year metastasis-free rate than others (79.3 vs. 93.5 %, P = 0.02). Proteins involved with NHEJ might have an influence on results of radiotherapy for uterine cervical cancer.

[Clinical Efficacy of Cepharanthin(R)for Radiotherapy-Induced Leukopenia - A Nationwide, Multicenter, and Observational Study].

The clinical efficacy and safety of cepharanthin for the treatment of radiotherapy-induced leukopenia were reevaluated at multiple institutions.Clinical data of cancer patients aged over 20 years old, who received a total radiotherapy dose above 40 Gy, and who were treated with cepharanthin for more than 2 weeks between April 2007 and November 2012, were evaluated. Data from 65 patients(males: 31, females: 34)from 7 facilities were analyzed to assess efficacy and adverse events.The mean leukocyte count was significantly higher at the end of the treatment compared with the initial data.However, no significant differences were observed in erythrocyte and platelet counts.No adverse events attributed to cepharanthin were reported.Although this was a retrospective study, cepharanthin was found to be safe and significantly effective for the management of leukopenia caused by radiotherapy.

Real-World Results of Stereotactic Body Radiotherapy for 399 Medically Operable Patients with Stage I Histology-Proven Non-Small Cell Lung Cancer.

Surgery is the standard treatment for stage I non-small cell lung cancer (NSCLC); however, no clear randomized trial demonstrates its superiority to stereotactic body radiotherapy (SBRT) regarding survival. We aimed to retrospectively evaluate the treatment outcomes of SBRT in operable patients with stage I NSCLC using a large Japanese multi-institutional database to show real-world outcome. Exactly 399 patients (median age 75 years; 262 males and 137 females) with stage I (IA 292, IB 107) histologically proven NSCLC (adenocarcinoma 267, squamous cell carcinoma 96, others 36) treated at 20 institutions were reviewed. SBRT was prescribed at a total dose of 48-70 Gy in 4-10 fractions. The median follow-up period was 38 months. Local progression-free survival rates were 84.2% in all patients and 86.1% in the T1, 78.6% in T2, 89.2% in adenocarcinoma, and 70.5% in squamous cell subgroups. Overall 3-year survival rates were 77.0% in all patients: 90.7% in females, 69.6% in males, and 41.2% in patients with pulmonary interstitial changes. Fatal radiation pneumonitis was observed in two patients, all of whom had pulmonary interstitial changes. This real-world evidence will be useful in shared decision-making for optimal treatment, including SBRT for operable stage I NSCLC, particularly in older patients.

Organs-at-risk dose constraints in head and neck intensity-modulated radiation therapy using a dataset from a multi-institutional clinical trial (JCOG1015A1).

BACKGROUND: JCOG1015A1 is an ancillary research study to determine the organ-specific dose constraints in head and neck carcinoma treated with intensity-modulated radiation therapy (IMRT) using data from JCOG1015. METHODS: Individual patient data and dose-volume histograms of organs at risk (OAR) were collected from 74 patients with nasopharyngeal carcinoma treated with IMRT who enrolled in JCOG1015. The incidence of late toxicities was evaluated using the cumulative incidence method or prevalence proportion. ROC analysis was used to estimate the optimal DVH cut-off value that predicted toxicities. RESULTS: The 5-year cumulative incidences of Grade (G) 1 myelitis, ≥ G1 central nervous system (CNS) necrosis, G2 optic nerve disorder, ≥ G2 dysphagia, ≥ G2 laryngeal edema, ≥ G2 hearing impaired, ≥ G2 middle ear inflammation, and ≥ G1 hypothyroidism were 10%, 5%, 2%, 11%, 5%, 26%, 34%, and 34%, respectively. Significant associations between DVH parameters and incidences of toxicities were observed in the brainstem for myelitis (D1cc ≥ 55.8 Gy), in the brain for CNS necrosis (D1cc ≥ 72.1 Gy), in the eyeball for optic nerve disorder (Dmax ≥ 36.6 Gy), and in the ipsilateral inner ear for hearing impaired (Dmean ≥ 44 Gy). The optic nerve, pharyngeal constrictor muscle (PCM), and thyroid showed tendencies between DVH parameters and toxicity incidence. The prevalence proportion of G2 xerostomia at 2 years was 17 versus 6% (contralateral parotid gland Dmean ≥ 25.8 Gy vs less). CONCLUSIONS: The dose constraint criteria were appropriate for most OAR in this study, although more strict dose constraints might be necessary for the inner ear, PCM, and brainstem.

Retrospective DVH analysis of point A based intracavitary brachytherapy for uterine cervical cancer.

Combining external beam radiotherapy (EBRT) with intracavitary brachytherapy (ICBT) is important for definitive treatment of cervical cancer. In cervical cancer patients receiving radiotherapy, we evaluated treatment outcomes in relation to dose-volume histogram parameters, including the computed tomography (CT)-based high-risk clinical target volume (HR-CTV) for ICBT. Between 2010 and 2015, 89 consecutive cervical cancer patients were mostly treated with 40 Gy of EBRT in 20 fractions and 18 Gy of ICBT prescribed to point A in 3 fractions. CT scans were obtained during ICBT. The HR-CTV D90 was calculated and the total doses of ICBT and EBRT were converted to the equivalent dose in 2 Gy fractions (EQD2). When the patients were divided into four groups according to EQD2 of the HR-CTV D90, the 3-year local recurrence-free survival rates were 95.2, 78.4, 52.7 and 42.9% for patients receiving >80 , 70-80 , 60-70 and <60 Gy, respectively. There was a significant negative correlation between EQD2 of the HR-CTV D90 and the HR-CTV volume at first ICBT (r = -0.713). Local recurrence was more frequent when the HR-CTV volume was ≥22 cc and EQD2 of the HR-CTV D90 was <70 Gy. Multivariate analysis showed that EQD2 of the HR-CTV D90 and concurrent chemotherapy (≥4 cycles) were significant determinants of overall survival. HR-CTV D90 was an important prognostic indicator for local recurrence. HR-CTV D90 >70 Gy is required for the better local control, especially in patients with a larger HR-CTV (≥22 cc at initial ICBT).

Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma.

Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti-programmed death 1 (PD-1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti-PD-1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti-PD-1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.

Brachytherapy for oral tongue cancer: an analysis of treatment results with various biological markers.

OBJECTIVE: Low-dose-rate (LDR) brachytherapy is an effective treatment for tongue cancer. However, little is known about the biological mechanism underlying this therapy, characterized by delivery of continuous exposures of LDR irradiation. It is reported that lower microvessel density (MVD), lower Ki-67 index or higher expression of endogenous hypoxic markers such as carbonic CA IX and Glut-1 are related to the poor control of tumors treated with external irradiation. To elucidate the biological characteristics of LDR brachytherapy, we analyzed our results in cases of tongue cancer treated with LDR brachytherapy by using immunohistochemical stainings with antibodies against Ki-67 and MVD, Glut-1 and CA IX. METHODS: The prognostic value of Ki-67 index, MVD and the expression of CA IX and Glut-1 was assessed in 68 tongue cancers treated with LDR brachytherapy. The specimens were taken from tongue cancers before radiation therapy and immunohistochemical staining was performed. RESULTS: The local recurrence-free survival rates were significantly different between T1+T2 and T3 (P = 0.00067), but not between low and high Ki-67 indexes (P = 0.54), between low and high MVD (P = 0.071), low and high CA IX indexes (P = 0.062) or low and high Glut-1 indexes (P = 0.107). T stage, the size of the tumor was the only significant factor for local control in multivariate analyses (P = 0.0377). CONCLUSION: LDR could overcome the radioresistence of non-cycling and hypoxic cells; however, we cannot draw firm conclusions due to the limited number of patients.

[Clinical application of altered fractionation theory].

Altered fractionation schedules are based on two different concepts of radiobiology. One concept is that the radiation repair capability of cells in late responding tissues is higher than that of cells in acute responding tissues which include tumor tissues. Hyperfractionation utilizes this concept. The other concept is that accelerated repopulation of tumor cells occurs in a later period of radiation therapy. In order to overcome repopulation of tumor cells, accelerated hyperfractionation is proposed. These two concepts are independent and some fractionation methods include both concepts. Clinical results of altered fractionation schedules of radiation therapy could be predicted with a biological model (the linear quadratic model theory)for fractionated radiation. When this biological model is applied to tumors in which the tumor cell repopulation during radiotherapy period is negligible, the correction for tumor proliferation is required. Since the calculation of the biological effect dose with this model uses several assumptions, we should consider the biological effect dose as a crude approximation. Especially, in case of concomitant chemotherapy and altered fractionation, it is difficult to predict its results with a simple radiobiology model. The randomized trial is required to examine the significance of chemoradiotherapy using altered fractionation.

Influence of PD-L1 expression in immune cells on the response to radiation therapy in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND AND PURPOSE: To investigate influences of proteins involved with tumor immunity on outcomes of radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). MATERIAL AND METHODS: We performed immunohistochemical staining to examine expressions of p16 and proteins involved with tumor immunity in 92 OPSCC patients treated with radiotherapy. RESULTS: Patients with abundant infiltrating CD8-positive cells had the significantly better overall survival (OS) rate than patients with fewer CD8-positive cells (p = 0.026). Patients with higher PD-L1 expression in tumor cells (TC 1-3) had a better outcome than those with low PD-L1 expression in tumor cells (TC 0) for both OS (p = 0.019) and progression-free survival (PFS) rate (p = 0.032). Patients with high PD-L1 expression in infiltrating immune cells (IC 3) showed significantly better OS (p = 0.009) and PFS (p = 0.011) than those with low PD-L1 expression (IC 0-2). Patients with p16-negative and IC 3 showed similar OS to patients with p16-positive and IC 0-2. P16-positive tumors had a significantly higher CD8-positive cell infiltration and PD-L1 expression in tumor cells than p16-negative tumors. CONCLUSIONS: In addition to tumor p16 expression, PD-L1 expression in TC and IC can be useful for predicting the response of OPSCC to radiotherapy.

Stereotactic Body Radiation Therapy for Patients with Pulmonary Interstitial Change: High Incidence of Fatal Radiation Pneumonitis in a Retrospective Multi-Institutional Study.

Pretreatment pulmonary interstitial change (PIC) has been indicated as a risk factor of severe radiation pneumonitis (RP) following stereotactic body radiation therapy (SBRT) for early-stage lung cancer, but details of its true effect remain unclear. This study aims to evaluate treatment outcomes of SBRT for stage I non-small cell lung cancer in patients with PIC. A total of 242 patients are included in this study (88% male). The median age is 77 years (range, 55⁻92 years). A total dose of 40⁻70 Gy is administered in 4 to 10 fractions during a 4-to-25 day period. One, two, and three-year overall survival (OS) rates are 82.1%, 57.1%, and 42.6%, respectively. Fatal RP is identified in 6.9% of all patients. The percent vital capacity <70%, mean percentage normal lung volume receiving more than 20 Gy (>10%), performance status of 2⁻4, presence of squamous cell carcinoma, clinical T2 stage, regular use of steroid before SBRT, and percentage predicting forced expiratory volume in one second (<70%) are associated with worse prognoses for OS. Our results indicate that fatal RP frequently occurs after SBRT for stage I lung cancer in patients with PIC.

Local tumor control and DNA-PK activity of peripheral blood lymphocytes in prostate cancer patients receiving radiotherapy.

Repair of DNA damage is critical for genomic stability, and DNA-dependent protein kinase (DNA-PK) has an important role in repairing double-strand breaks. We examined whether the DNA-PK activity of peripheral blood lymphocytes (PBLs) was related to biochemical (prostate-specific antigen: PSA) relapse and radiation toxicity in prostate cancer patients who have received radiotherapy. A total of 69 patients with localized adenocarcinoma of the prostate participated in this study. Peripheral blood was collected 2 years or later after radiotherapy and centrifuged, then DNA-PK activity was measured by a filter binding assay. The high DNA-PK activity group had a significantly higher PSA relapse-free survival rate than the low DNA-PK activity group. The 10-year PSA relapse-free survival was 87.0% in the high DNA-PK activity group, whereas it was 52.7% in the low DNA-PK activity group. Multivariate analysis showed the Gleason score and the level of DNA-PK activity were significant predictors of PSA relapse after radiotherapy. In addition, the low DNA-PK activity group tended to have a higher incidence of Grade 1-2 urinary toxicity than the high DNA-PK activity group. Prostate cancer patients with low DNA-PK activity had a higher rate of PSA relapse and a higher incidence of urinary toxicity. DNA-PK activity in PBLs might be a useful marker for predicting PSA relapse and urinary toxicity, possibly contributing to personalized treatment of prostate cancer.

Multi-institutional analysis of early squamous cell carcinoma of the hypopharynx treated with radical radiotherapy.

PURPOSE: To analyze the outcomes of patients with early hypopharyngeal cancer treated with radical radiotherapy (RT). METHODS AND MATERIALS: Ten institutions combined the data from 115 patients with Stage I-II hypopharyngeal squamous cell carcinoma treated with definitive RT between 1990 and 2001. The median patient age was 67 years; 99 patients were men and 16 were women. Of the 115 patients, 39 had Stage I and 76 had Stage II disease. Conventional fractionation was used in 98 patients and twice-daily RT in 17 patients; chemotherapy was combined with RT in 57 patients. The median follow-up period was 47 months. RESULTS: The overall and disease-specific 5-year survival rate for 95 patients without synchronous malignancies was 66.0% and 77.4%, respectively. The 5-year disease-specific survival rate by T stage was 95.8% for patients with T1 disease and 70.1% for patients with T2 disease (p=0.02). Of the 115 patients, local control with laryngeal voice preservation was achieved in 34 of 39 patients with T1 lesions, including 7 patients successfully salvaged, and in 56 of 76 patients with T2 lesions. Sixty-five patients (56.5%) had synchronous or metachronous cancers. Of the 115 patients, 19 died of hypopharyngeal cancer, 10 died of second primary cancers, and 14 died of other causes during the study and follow-up periods. CONCLUSIONS: Patients with early hypopharyngeal cancer tended to have a good prognosis after RT. However, second malignancies had an adverse effect on the overall outcomes of patients with early hypopharyngeal cancer.

Three cases of diffuse large B-cell lymphoma of the mandible treated with radiotherapy and chemotherapy.

CASE REPORT: We report three cases of diffuse large B-cell lymphoma of the mandible and a review of the literature. All 3 of our patients had stage I AE disease and had complete remission for more than 2 years after 42-46 Gy of irradiation to the primary tumor with regional lymph nodes and 3 courses of chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, and predonisolone (CHOP). Literature analysis, although biased toward published data, indicated that the 3-year disease-specific survival rates for non-Hodgkin's lymphoma (NHL) of the mandible were 90.5% and 47.6% for stages I and II, respectively. The treatment results for NHL of the mandible may be similar to general primary bone NHL and to other extranodal NHL's. CONCLUSION: Radiotherapy alone is not sufficient for tumor control for stage I+II, disease, and combination chemotherapy may be needed.

Results and DVH analysis of late rectal bleeding in patients treated with 3D-CRT or IMRT for localized prostate cancer.

In patients undergoing radiotherapy for localized prostate cancer, dose-volume histograms and clinical variables were examined to search for correlations between radiation treatment planning parameters and late rectal bleeding. We analyzed 129 patients with localized prostate cancer who were managed from 2002 to 2010 at our institution. They were treated with 3D conformal radiation therapy (3D-CRT, 70 Gy/35 fractions, 55 patients) or intensity-modulated radiation therapy (IMRT, 76 Gy/38 fractions, 74 patients). All radiation treatment plans were retrospectively reconstructed, dose-volume histograms of the rectum were generated, and the doses delivered to the rectum were calculated. Time to rectal bleeding ranged from 9-53 months, with a median of 18.7 months. Of the 129 patients, 33 patients had Grade 1 bleeding and were treated with steroid suppositories, while 25 patients with Grade 2 bleeding received argon plasma laser coagulation therapy (APC). Three patients with Grade 3 bleeding required both APC and blood transfusion. The 5-year incidence rate of Grade 2 or 3 rectal bleeding was 21.8% for the 3D-CRT group and 21.6% for the IMRT group. Univariate analysis showed significant differences in the average values from V65 to V10 between Grades 0-1 and Grades 2-3. Multivariate analysis demonstrated that patients with V65 ≥ 17% had a significantly increased risk (P = 0.032) of Grade 2 or 3 rectal bleeding. Of the 28 patients of Grade 2 or 3 rectal bleeding, 17 patients (60.7%) were cured by a single session of APC, while the other 11 patients required two sessions. Thus, none of the patients had any further rectal bleeding after the second APC session.

Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. MATERIALS AND METHODS: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. RESULTS: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. CONCLUSION: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.