Reirradiation for recurrent gynecologic cancer using high-dose-rate brachytherapy in Japan: A multicenter survey on practice patterns and outcomes.

BACKGROUND AND PURPOSE: The aim of the study is to examine the present status of reirradiation with high-dose-rate (HDR) brachytherapy for recurrent gynecologic cancer in Japan and to determine the role of this therapy in clinical practice. MATERIALS AND METHODS: A retrospective multicenter chart review was performed for reirradiation for gynecologic cancer using HDR brachytherapy. Each center provided information on patient characteristics, treatment outcomes, and complications. RESULTS: The study included 165 patients treated at 9 facilities from 2000 to 2018. The analysis of outcomes included 142 patients treated with curative intent. The median follow-up time for survivors was 30 months (range 1-130 months). The 3-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 53 % (95 %CI: 42-63 %), 44 % (35-53 %), and 61 % (50-70 %) for cervical cancer; 100 % (NA), 64 % (30-85 %), and 70 % (32-89 %) for endometrial cancer; and 54 % (13-83 %), 38 % (6-72 %), and 43 % (6-78 %) for vulvar and vaginal cancer, respectively. In multivariate analysis, interval to reirradiation (<1 year) was a significant risk factor for OS, PFS and LC; Gross Tumor Volume (≥25 cm3) was a significant risk factor for OS. Toxicities were analyzed in all enrolled patients (n = 165). Grade ≥ 3 late toxicities occurred in 49 patients (30 %). A higher cumulative EQD2 (α/ß = 3) was significantly associated with severe complications. CONCLUSION: Reirradiation with HDR brachytherapy for recurrent gynecologic cancer is effective, especially in cases with a long interval before reirradiation.

Are prophylactic antibiotics required for combined intracavitary and interstitial brachytherapy of gynecologic cancers?

The purpose of this study is to evaluate the need for prophylactic antibiotic treatment prior to combined intracavitary and interstitial (hybrid) brachytherapy for gynecologic cancer. A total of 105 gynecologic cancer patients received 405 brachytherapy sessions, including 302 sessions of intracavitary brachytherapy and 103 sessions of hybrid brachytherapy. Prophylactic antibiotics were administered before 35% of the hybrid brachytherapy sessions. The incidence of postbrachytherapy fever and the frequency of subsequent antibiotic use for infection were compared between treatment groups. Among patients treated with hybrid brachytherapy, fever ≥37.5°C occurred in 16.4% of those not receiving prophylactic antibiotics and 16.7% of those receiving prophylactic antibiotics (P > 0.05). Similarly, fever ≥38.0°C occurred in 4.9% of patients not receiving prophylactic antibiotics and 2.4% of those receiving prophylactic antibiotics (P > 0.05). Additional antibiotics were used to treat postbrachytherapy infections in 4.8% of the group receiving prophylactic antibiotics and 0% of those not receiving prophylactic antibiotics, again without statistically significant difference. There were also no significant differences in posttreatment fever incidence and antibiotics use for infection between intracavitary brachytherapy and hybrid brachytherapy sessions. In conclusion, the incidences of infection and fever are low following hybrid brachytherapy, so prophylactic antibiotics are generally unnecessary.

Adenoid cystic carcinoma of the orbit without lacrimal gland involvement and with intracranial extension: A case report.

We present a 76-year-old female with a 6-year history of decreased vision in the right eye and right-sided facial neuralgia. She had a T1 isointense and T2 isointense enhancing lesion in the right orbit and the middle cranial fossa on MRI examination. Granulomatous disease or meningioma was suspected, however, after removal, the tumor was identified by pathology as adenoid cystic carcinoma (ACC). The tumor has no radiological and clinical lacrimal grand involvement. ACC shows a slow and indolent growth pattern but is associated with poor long-term outcomes, mainly due to perineural invasion, local control failure, and distant metastasis. This case highlights the importance of a pathologic diagnosis and early intervention in similar presentations.

Conversion from dose length product to effective dose for the CT component of whole-body PET/CT.

OBJECTIVE: For dose management of CT, the ratio of effective dose (ED) to dose length product (DLP) is often used to convert DLP to ED. We evaluated this ratio in the CT component of whole-body PET/CT performed under various imaging conditions to determine a practical method for ED estimation applicable to PET/CT. METHODS: In total, 400 patients who underwent whole-body PET/CT were enrolled. The imaging conditions were variable in terms of the scanner model, setting of automatic exposure control (AEC) setting and arm positioning. The scan range was divided into six anatomical regions. DLP was calculated for each region, and multiplied by the conversion factor for the respective region to determine regional ED. The six regional EDs were summed together to determine ED by the regional DLP method (EDrDLP). Additionally, regional ED was assessed using CT-Expo, software dedicated to CT dose estimation, and the total of six regional EDs were defined as ED by the CT-Expo method (EDCT-Expo). EDrDLP/DLP and EDCT-Expo/DLP were calculated using DLP automatically provided by the scanner. RESULTS: EDrDLP/DLP ranged from 0.0121 to 0.0128 mSv/mGy/cm with the arms up and from 0.0127 to 0.0134 mSv/mGy/cm with the arms down. Putting the arms down slightly increased EDrDLP/DLP, presumably due to an increased contribution of the chest and abdomen to total radiation exposure. The AEC setting and scanner model also influenced EDrDLP/DLP significantly but slightly. EDCT-Expo/DLP showed apparent scanner dependence, which appeared mainly attributable to differences in the constants used for DLP calculation between the scanner and CT-Expo. CONCLUSION: Multiplication of scanner-derived DLP by a conversion factor of 0.013 mSv/mGy/cm provides acceptable ED estimates.

Intensity-Modulated Radiation Therapy with Simultaneous Integrated Boost for Clinically Node-Positive Prostate Cancer: A Single-Institutional Retrospective Study.

This study aimed to evaluate clinical outcomes and the toxicity of intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) combined with androgen-deprivation therapy for clinically node-positive (cN1) prostate cancer. We retrospectively analyzed 97 patients with cN1 prostate cancer who received SIB-IMRT between June 2008 and October 2017 at our hospital. The prescribed dosages delivered to the prostate and seminal vesicle, elective node area, and residual lymph nodes were 69, 54, and 60 Gy in 30 fractions, respectively. Kaplan-Meier analysis was used to determine 5-year biochemical relapse-free survival (bRFS), relapse-free survival (RFS), overall survival (OS), and prostate cancer-specific survival (PCSS). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. Over a median follow-up duration of 60 months, the 5-year bRFS, RFS, OS, and PCSS were 85.1%, 88.1%, 92.7% and 95.0%, respectively. Acute Grade 2 genito-urinary (GU) and gastro-intestinal (GI) toxicities were observed in 10.2% and 2.1%, respectively, with no grade ≥3 toxicities being detected. The cumulative incidence rates of 5-year Grade ≥2 late GU and GI toxicities were 4.7% and 7.4%, respectively, with no Grade 4 toxicities being detected. SIB-IMRT for cN1 prostate cancer demonstrated favorable 5-year outcomes with low incidences of toxicity.

Dose constraints in the rectum and bladder following carbon-ion radiotherapy for uterus carcinoma: a retrospective pooled analysis.

BACKGROUND: Carbon-ion radiotherapy (C-ion RT) provides better dose distribution in cancer treatment compared to photons. Additionally, carbon-ion beams provide a higher biological effectiveness, and thus a higher tumor control probability. However, information regarding the dose constraints for organs at risk in C-ion RT is limited. This study aimed to determine the predictive factors for late morbidities in the rectum and bladder after carbon-ion C-ion RT for uterus carcinomas. METHODS: Between June 1995 and January 2010, 134 patients with uterus carcinomas were treated with C-ion RT with curative intent; prescription doses of 52.8-74.4 Gy (relative biological effectiveness) were delivered in 20-24 fractions. Of these patients, 132 who were followed up for > 6 months were analyzed. We separated the data in two subgroups, a 24 fractions group and a 20 fractions group. Late morbidities, proctitis, and cystitis were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. The correlations of clinical and dosimetric parameters, V10-V60, D5cc, D2cc, and Dmax, with the incidence of ≥grade 1 morbidities were retrospectively analyzed. RESULTS: In the 24 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 64 and 9%, respectively. In addition, in the 20 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 32 and 19%, respectively. Regarding the dose-volume histogram data on the rectum, the D5cc and D2cc were significantly higher in patients with ≥grade 1 proctitis than in those without morbidity. In addition, the D5cc for the bladder was significantly higher in patients with ≥grade 1 cystitis than in those without morbidity. Results of univariate analyses showed that D2cc of the rectum was correlated with the development of ≥grade 1 late proctitis. Moreover, D5cc of the bladder was correlated with the development of ≥grade 1 late cystitis. CONCLUSIONS: The present study identified the dose-volume relationships in C-ion RT regarding the occurrence of late morbidities in the rectum and bladder. Assessment of the factors discussed herein would be beneficial in preventing late morbidities after C-ion RT for pelvic malignancies. TRIAL REGISTRATION: Retrospectively registered ( NIRS: 16-040 ).

Radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma: long-term outcomes over 10 years.

This study aimed to assess the long-term outcomes of radiotherapy in patients with localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty-seven patients with Stage I gastric MALT lymphoma were treated with radiotherapy from 1999 to 2010. The median age was 65 years (range: 31-84). Fifteen patients were Helicobacter pylori-negative. Thirteen patients were treated with definitive radiotherapy alone. The other 14 patients who had refractory or residual disease following a prior treatment received salvage radiotherapy. The median dose of the radiotherapy was 30 Gy in 20 fractions (range: 30-39.5 Gy). The median follow-up period was 121 months (range: 8-176 months). The 5- and 10-year overall survival rates for all patients were 92% and 87%, respectively. No patients died from MALT lymphoma. Three patients died of other diseases at 8, 33 and 74 months after radiotherapy (myocardial infarction, pneumonia and hepatocellular carcinoma, respectively). No cases of local recurrence were observed during the follow-up period. There were no serious late gastric, liver or kidney complications during a median follow-up period of over 10 years. Two patients remain alive with distant metastases: a lung metastasis and an abdominal lymph node metastasis at 104 months and 21 months after radiotherapy, respectively. Excellent long-term local control was observed in patients with localized gastric MALT lymphoma after radiotherapy. However, lifelong follow-up should be conducted to detect cases of late recurrence, especially distant metastases.

In-room computed tomography-based brachytherapy for uterine cervical cancer: results of a 5-year retrospective study.

Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography-based brachytherapy. Eighty patients with Stage IB1-IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20-40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced-stage patients aged ≤75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III-IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III-IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage.

Regulation of Unfolded Protein Response via Protein S-nitrosylation.

Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation. Previously we demonstrated that protein disulfide isomerase (PDI) is S-nitrosylated in brains manifesting sporadic neurodegenerative diseases. This modification results in dysfunction of its enzymatic activity and consequently the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). The aim of this study was to clarify the detailed function of NO on unfolded protein response (UPR) branches. We here found that the ER stress sensor IRE1α is S-nitrosylated. Interestingly, NO specifically abrogates ribonuclease activity, but not oligomerization or autophosphorylation of IRE1α. Site-directed mutagenesis revealed that Cys 931 and Cys951 in IRE1 are targets for S-nitrosylation. These mutants expressing in IRE1α knockout MEF showed a resistant role to the inhibition of nuclease activity by NO. Thus, we elucidated the effects of S-nitrosylation on ER stress sensors that mediate the UPR, and thus contribute to cell death pathways.

Favorable outcome of intraoperative radiotherapy to the primary site in patients with metastatic prostate cancer.

BACKGROUND: The aim of this study was to determine whether local radiotherapy to the prostate by intraoperative radiotherapy (IORT) increases the overall and cancer-specific survival rates of patients with metastatic prostate cancer. METHODS: Between 1993 and 2000, 102 patients with prostate cancer were treated with a combination of (a) IORT of the prostate (25 or 30 Gy per fraction); (b) external beam radiotherapy of the prostate (30 Gy in 10 fractions), starting approximately 1 week post-operatively; and (c) endocrine treatment. Of these, 16 patients had stage D1 disease (D1 IORT group), 32 had stage D2 disease without visceral metastasis (D2 IORT group), and 38 had stage D2 disease without visceral metastasis and did not receive local therapy (D2 control group). Overall and cancer-specific survival rates were compared. RESULTS: The 5- and 10-year cancer-specific survival rates were 75.9 and 52.7 %, respectively, in the (D1 + D2) IORT group and 45.8 and 33.5 %, respectively, in the D2 control group, with cancer-specific survival being significantly longer in the D2 IORT than in the D2 control group (P = 0.030). Univariate and multivariate reduced-rank regression analyses showed that extent of skeletal disease Grade 4 and non-regional lymph node metastasis were significantly prognostic of poorer cancer-specific survival (P < 0.001 each). CONCLUSIONS: Local radiotherapy to the prostate by IORT in patients with metastatic prostate cancer may contribute to better survival, especially in patients without extent of skeletal disease Grade 4 or non-regional lymph node metastasis.

Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress.

Protein S-nitrosylation modulates important cellular processes, including neurotransmission, vasodilation, proliferation, and apoptosis in various cell types. We have previously reported that protein disulfide isomerase (PDI) is S-nitrosylated in brains of patients with sporadic neurodegenerative diseases. This modification inhibits PDI enzymatic activity and consequently leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen. Here, we describe S-nitrosylation of additional ER pathways that affect the unfolded protein response (UPR) in cell-based models of Parkinson's disease (PD). We demonstrate that nitric oxide (NO) can S-nitrosylate the ER stress sensors IRE1α and PERK. While S-nitrosylation of IRE1α inhibited its ribonuclease activity, S-nitrosylation of PERK activated its kinase activity and downstream phosphorylation/inactivation or eIF2α. Site-directed mutagenesis of IRE1α(Cys931) prevented S-nitrosylation and inhibition of its ribonuclease activity, indicating that Cys931 is the predominant site of S-nitrosylation. Importantly, cells overexpressing mutant IRE1α(C931S) were resistant to NO-induced damage. Our findings show that nitrosative stress leads to dysfunctional ER stress signaling, thus contributing to neuronal cell death.

Clinical outcomes of helical tomotherapy for super-elderly patients with localized and locally advanced prostate cancer: comparison with patients under 80 years of age.

We investigated the clinical outcomes of helical tomotherapy in 23 patients aged ≥80 years with localized and locally advanced prostate cancer and compared the results with data from 171 patients under 80 years. All patients received helical tomotherapy in our hospital between September 2009 and October 2012. The median follow-up periods were 35 months in the aged group and 34 months in the younger group. The median prescribed dose in helical tomotherapy was 78 Gy in 39 fractions (range, 72-78 Gy). The 3-year overall survival and biochemical relapse-free rates were 92% and 96% in the aged group and 99.4% and 97.3% in the younger group, respectively. There was no significant difference between the two groups in the biochemical relapse-free rates. The 3-year cumulative incidences of late Grade 2 or higher rectal toxicity and urinary toxicity were 13% and 4.8% in the aged group and 7.0% and 1.2% in the younger group, respectively. There was no significant difference between the aged group and the younger group in the cumulative incidence rates of rectal toxicity or urinary toxicity. No patients exhibited Grade 4 or higher toxicity, and all patients improved with conservative therapy. Helical tomotherapy in super-elderly patients with localized and locally advanced prostate cancer had good biochemical control rates without severe late toxicity. Definitive helical tomotherapy may be the treatment of choice for patients with localized and locally advanced prostate cancer, even in those older than 80 years of age.

Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats.

Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-ß1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-ß1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury.

Changes in bone mineral density in uterine cervical cancer patients after radiation therapy.

PURPOSE: To prospectively investigate the changes in bone mineral density (BMD) after pelvic radiation therapy in patients with uterine cervical cancer. METHODS AND MATERIALS: Of 52 cervical cancer patients who received pelvic RT in our university hospital between 2009 and 2011, 46 patients without recurrence and who were followed up for more than 12 months were included in the study. The BMD of the irradiated region and nonirradiated regions, serum estradiol, tartrate-resistant acid phosphatase-5b, and N-terminal cross-linking telopeptide of collagen 1 were measured before, at 3 months after, and at 12 months after RT. The patient cohort was divided into 2 groups according to estradiol level before RT, and the groups were defined as postmenopausal (<40 pg/mL) and premenopausal (≥40 pg/mL). RESULTS: The mean BMDs within the irradiation field (lumbar vertebra 5) in the postmenopausal and the premenopausal groups were 0.825 and 0.910 g/cm(2) before RT and 0.746 and 0.841 g/cm(2) 12 months after RT, respectively. Significant decreases were observed in both groups (P<.05 and P<.01, respectively). In addition, in the premenopausal group the mean BMDs of the nonirradiated regions at thoracic vertebrae 9-12 and lumbar vertebrae 2-4 were 0.753 and 0.958 g/cm(2) before RT and were significantly decreased to 0.706 and 0.921 g/cm(2) 12 months after RT (P<.01 and P<.05, respectively). Estradiol significantly decreased 3 months after RT, whereas tartrate-resistant acid phosphatase-5b and N-terminal cross-linking telopeptide of collagen 1 continued to increase over time in the premenopausal group. CONCLUSIONS: A decrease in BMD in the irradiated region after RT was observed within 1 year, regardless of menopausal status. Furthermore, in premenopausal patients, pelvic RT caused a decrease in systemic BMD.

Interfractional change of high-risk CTV D90 during image-guided brachytherapy for uterine cervical cancer.

The purpose of this study was to evaluate interfractional changes of the minimum dose delivered to 90% of the high-risk clinical target volume (HR-CTV D90) and D2cc of the bladder and rectum during brachytherapy for uterine cervical cancer patients. A total of 52 patients received external beam radiotherapy and high-dose-rate intracavitary brachytherapy (ICBT). For each of four ICBT applications, a pelvic CT scan was performed and the HR-CTV was delineated. Retrospectively, these patients were divided into two groups: (i) the standard dose group with 6 Gy to point A in each ICBT, and (ii) the adaptive dose group with a modified dose to point A to cover the HR-CTV with the 6-Gy isodose line as much as possible. The HR-CTV D90 was assessed in every session, and analyzed as interfractional changes. In the standard dose group, the interfractional changes of the HR-CTV D90 showed a linear increase from the first to the third of the four ICBT (average 6.1, 6.6, 7.0 and 7.1 Gy, respectively). In contrast, those of the adaptive dose group remained almost constant (average 7.2, 7.2, 7.3 and 7.4 Gy, respectively). Especially, in the case of a large HR-CTV volume (≥35 cm(3)) at first ICBT, the total HR-CTV D90 of the adaptive dose group with brachytherapy was significantly higher than that of the standard dose group. There were no significant differences in total D2cc in bladder and rectum between the two groups. Image-guided adaptive brachytherapy based on interfractional tumor volume change improves the dose to the HR-CTV while keeping rectal and bladder doses within acceptable levels.

Granulocyte-colony stimulating factor-producing cervical cancers treated with carbon-ion irradiation.

Granulocyte-colony stimulating factor (G-CSF)-producing tumor is a rare condition. It has an aggressive nature and shows resistance to conventional treatments. We report two cases of G-CSF-producing uterine cervical cancer who were successfully treated with carbon-ion radiotherapy (C-ion RT). The first case was a 76-year-old woman with stage IIIB uterine cervical cancer, and the second was a 75-year-old woman with bulky stage IIB disease. Prior to treatment, both patients presented severe granulocytosis and elevated serum G-CSF concentrations. After C-ion RT, their cervical tumors completely disappeared, and their granulocytosis and elevated serum G-CSF levels improved as well. C-ion RT has been reported to be effective for various aggressive tumors, and it may be a good treatment option for this rare aggressive tumor.

Carbon-ion radiotherapy for marginal lymph node recurrences of cervical cancer after definitive radiotherapy: a case report.

Recurrences of cervical cancer after definitive radiotherapy often occur at common iliac or para-aortic lymph nodes as marginal lymph node recurrences. Patients with these recurrences have a chance of long-term survival by optimal re-treatment with radiotherapy. However, the re-irradiation often overlaps the initial and the secondary radiotherapy fields and can result in increased normal tissue toxicities in the bowels or the stomach. Carbon-ion radiotherapy, a form of particle beam radiotherapy using accelerated carbon ions, offers more conformal and sharp dose distribution than X-ray radiotherapy. Therefore, this approach enables the delivery of high radiation doses to the target while sparing its surrounding normal tissues. Marginal lymph node recurrences in common iliac lymph nodes after radiotherapy were treated successfully by carbon-ion radiotherapy in two patients. These two patients were initially treated with a combination of external beam radiotherapy and intracavitary and interstitial brachytherapy. However, the diseases recurred in the lymph nodes near the border of the initial radiotherapy fields after 22 months and 23 months. Because re-irradiation with X-ray radiotherapy may deliver high doses to a section of the bowels, carbon-ion radiotherapy was selected to treat the lymph node recurrences. A total dose of 48 Gy (RBE) in 12 fractions over 3 weeks was given to the lymph node recurrences, and the tumors disappeared completely with no severe acute toxicities. The two patients showed no evidence of disease for 75 months and 63 months after the initial radiotherapy and for 50 months and 37 months after the carbon-ion radiotherapy, respectively. No severe late adverse effects are observed in these patients. The two presented cases suggest that the highly conformal dose distribution of carbon-ion radiotherapy may be beneficial in the treatment of marginal lymph node recurrences after radiotherapy. In addition, the higher biological effect of carbon-ion radiotherapy and its superior dose distribution may provide more effective tumor control in treatment for re-irradiation of the marginal recurrences in radiation resistant tumors other than cervical cancer.

Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma.

Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen-specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n=88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation.

Dose volume analysis of radiotherapy for inoperable patients with stage I-II endometrial carcinoma.

This study aims to assess the efficacy and toxicity of definitive radiotherapy for early-stage endometrial carcinoma. The correlation between CT-based dosimetric parameters and clinical outcomes is also evaluated. Between 2002 and 2006, 10 medically inoperable patients with T1-2 endometrial carcinoma were treated with radiotherapy alone. A combination of external beam radiotherapy (EBRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT) was used for 9 patients, and one was treated with HDR-ICBT alone. Dose prescription of HDR-ICBT was determined in reference to CT images at brachytherapy, and a total dose of 22-24 Gy in 4 fractions was delivered to the outer perimeter of the uterine corpus. Dose-volume parameters of the gross tumor volume (GTV), clinical target volume (CTV), and organs at risk were assessed retrospectively using the dose-volume histograms derived from the CT image-based treatment planning system. After a median follow-up of 55 months, 9 patients were alive without evidence of recurrence. One patient died from liver cirrhosis 17 months after radiotherapy. Severe acute and late toxicities were not observed in any of the patients. Average minimum dose to 90% of GTV and CTV (D90) was 88.0 and 45.9 Gy(EQD2), respectively. The minimum dose delivered to 2 cc of the most irradiated volumes of the rectum and sigmoid colon (D(2cc)) was 78.9 and 65.9 Gy(EQD2), respectively. These patients developed Grade 1 late complications. In this study, stage I-II endometrial carcinoma was well-controlled locally with minimum late toxicity by radiotherapy alone with HDR-ICBT. 3D image-based brachytherapy may potentially deliver a sufficiently high dose to the whole tumor without significant increase in dose to surrounding normal tissues.

Combining carbon ion radiotherapy and local injection of α-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model.

PURPOSE: Our previous report indicated that carbon ion beam irradiation upregulated membrane-associated immunogenic molecules, underlining the potential clinical application of radioimmunotherapy. The antimetastatic efficacy of local combination therapy of carbon ion radiotherapy and immunotherapy was examined by use of an in vivo murine model. METHODS AND MATERIALS: Tumors of mouse squamous cell carcinoma (NR-S1) cells inoculated in the legs of C3H/HeSlc mice were locally irradiated with a single 6-Gy dose of carbon ions (290 MeV/nucleon, 6-cm spread-out Bragg peak). Thirty-six hours after irradiation, α-galactosylceramide-pulsed dendritic cells (DCs) were injected into the leg tumor. We investigated the effects on distant lung metastases by counting the numbers of lung tumor colonies, making pathologic observations, and assessing immunohistochemistry. RESULTS: The mice with no treatment (control) presented with 168 ± 53.8 metastatic nodules in the lungs, whereas the mice that received the combination therapy of carbon ion irradiation and DCs presented with 2.6 ± 1.9 (P = 0.009) at 2 weeks after irradiation. Immunohistochemistry showed that intracellular adhesion molecule 1, which activates DCs, increased from 6 h to 36 h after irradiation in the local tumors of the carbon ion-irradiated group. The expression of S100A8 in lung tissue, a marker of the lung pre-metastatic phase, was decreased only in the group with a combination of carbon ions and DCs. CONCLUSIONS: The combination of carbon ion radiotherapy with the injection of α-galactosylceramide-pulsed DCs into the primary tumor effectively inhibited distant lung metastases.