Search

Supplementary Figure 1 from BRCA1-Associated Protein 1 Interferes with BRCA1/BARD1 RING Heterodimer Activity

This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important.

In this study, we evaluate the analgesic effect of strontium-89 (Sr-89) for patients with breast cancer having multiple bone metastases and identify positive predictive factors. We retrospectively evaluated 15 patients who were administered Sr-89 for painful bone metastases from breast cancer at St. Marianna University Hospital between January 2010 and April 2014. For patients receiving multiple doses, only the first dose was evaluated. Pain relief was defined as a decrease in the score of the Numeric Rating Scale (NRS) or requirement of reduced doses of pain medication 1 - 2 months after being on Sr-89 administration. The associations between pain relief owing to Sr-89 and that owing to bone scan index, interval from bone metastasis onset to Sr-89 administration, zoledronate and denosumab treatment history, hormone therapy/aromatase inhibitor history, and chemotherapy history were assessed. A logistic model was used for statistical analysis. Pain relief was observed in 11 (73.3%) of 15 patients. No statistically significant value was observed between pain relief and bone scan index, interval from bone metastasis onset to Sr-89 administration, zoledronate and denosumab treatment history, hormone therapy/aromatase inhibitor history, and chemotherapy. Thus, Sr-89 was effective for 70% of patients with breast cancer bone metastases, although positive predictive factors for pain relief could not be determined.

Purpose: The aim of this study was to analyze the treatment outcomes of alternating chemoradiotherapy (ACRT) for nasopharyngeal carcinoma (NPC) and to assess the safety and ef 昀c c of this treatment. Materials and Methods: Twelve patients with stage II–IVB NPC were treated with ACRT in our hospital be‐ tween 2005 and 2011. The radiotherapy period was divided into two components. In the 昀rst half, patients re‐ ceived 36 Gy to the whole neck 昀eld. In the second half, patients received 30~34.2Gy to the shrinking 昀eld to the primary and involved lymph nodes. A course of chemotherapy comprised of 昀uorour cil at a dose of 800 mg/m 2 /day was administered for 5 days (day 1–5), and cisplatin at 50 mg/m 2 /day was administered for 2 days (day 6–7). A total of three courses of chemotherapy were performed systemically before starting radiotherapy, after completing the 昀rst half of radiotherapy and after completing the second half of radiotherapy. Results: The planned radiation dose was achieved for all patients. Ten of the 12 patients completed the three courses of chemotherapy as planned. The remaining two patients completed only two courses because they re‐ fused, not due to adverse events. The 昀ve- e r overall survival rate was 83%, the progression-free survival rate was 67%, the locoregional progression-free survival rate was 75%, and the distant-metastasis free survival rate was 92%. With regard to acute adverse events, the incidence of grade ≧3 hematotoxicity was 33%, and the nonhematotoxicity event was only one case of grade 3 mucositis. No late adverse events of grade ≧3 occurred. Conclusion: ACRT offered an excellent completion rate and could be safely conducted. Although a limited numbers of subjects were considered in this study, the outcomes of ACRT were favorable in terms of safety and ef 昀c c .

We investigated the factors predicting radiation-induced organizing pneumonia (RIOP) relapse after tangential breast irradiation. The participants included 23 patients diagnosed with RIOP at the St. Marianna University School of Medicine Hospital between January 2008 and March 2015. Relapse was defined as the appearance of new lesions on diagnostic images during follow-up or after commencing treatment. The relapse-free survival rate and the following 9 parameters were compared between patients with and without RIOP relapse: 1) age (less than vs. equal to or more than the median); 2) white blood cell count (less than vs. equal to or more than the median); 3) C-reactive protein (CRP) level at the time of RIOP diagnosis (less than normal, more than normal/ less than borderline, and more than borderline); 4) boost irradiation (yes vs. no); 5) maximum lung depth on linacgraphy (less than vs. equal to or more than the median); 6) hormone therapy (yes vs. no); 7) chemotherapy (yes vs. no); 8) RIOP ratio in the whole lung (less than vs. equal to or more than the median) at the time of RIOP diagnosis; and 9) use of corticosteroids (yes vs. no). The Kaplan-Meier method was used for statistical analysis, with relapse as the cutoff. The follow-up period spanned the date of RIOP onset to May 30, 2015. The level of significance for 2-sided tests was p < 0.05. Relapse was evident in 14 patients (60.8%). The relapse-free survival rate was significantly greater in the normal CRP group (less than 0.30 mg/dl) than in the abnormal CRP group (more than 0.36 mg/dl) (p = 0.044) and in the normal/borderline CRP group (less than 0.36 mg/dl) than in the high CRP group (more than 0.70 mg/dl) (p < 0.01). The CRP level at RIOP onset may be a useful predictor of relapse after breast-conserving therapy.We investigated the factors predicting radiation-induced organizing pneumonia (RIOP) relapse after tangential breast irradiation. The participants included 23 patients diagnosed with RIOP at the St. Marianna University School of Medicine Hospital between January 2008 and March 2015. Relapse was defined as the appearance of new lesions on diagnostic images during follow-up or after commencing treatment. The relapse-free survival rate and the following 9 parameters were compared between patients with and without RIOP relapse: 1) age (less than vs. equal to or more than the median); 2) white blood cell count (less than vs. equal to or more than the median); 3) C-reactive protein (CRP) level at the time of RIOP diagnosis (less than normal, more than normal/ less than borderline, and more than borderline); 4) boost irradiation (yes vs. no); 5) maximum lung depth on linacgraphy (less than vs. equal to or more than the median); 6) hormone therapy (yes vs. no); 7) chemotherapy (yes vs. no); 8) RIOP ratio in the whole lung (less than vs. equal to or more than the median) at the time of RIOP diagnosis; and 9) use of corticosteroids (yes vs. no). The Kaplan-Meier method was used for statistical analysis, with relapse as the cutoff. The follow-up period spanned the date of RIOP onset to May 30, 2015. The level of significance for 2-sided tests was p < 0.05. Relapse was evident in 14 patients (60.8%). The relapse-free survival rate was significantly greater in the normal CRP group (less than 0.30 mg/dl) than in the abnormal CRP group (more than 0.36 mg/dl) (p = 0.044) and in the normal/borderline CRP group (less than 0.36 mg/dl) than in the high CRP group (more than 0.70 mg/dl) (p < 0.01). The CRP level at RIOP onset may be a useful predictor of relapse after breast-conserving therapy.

We report a case of a patient who demonstrated long-term survival following completion of concurrent chemoradiotherapy (CCRT) for stage IVB advanced uterine cervical cancer. When the patient was referred to us, her radiological findings showed para-aortic and supraclavicular lymph node (SCN) metastases. The CCRT for primary lesions and para-aortic lymph node (PAN) were performed, followed by radiotherapy for SCN, re‐ sulting in successful control of the lesions. After five and a half years of strict follow-up, recurrent PAN was observed with PET-CT. Systemic chemotherapy was re-stored and controlled recurrent PAN without signs of serious adverse events. The patient has showed no recurrent signs with any related symptoms for the past 8 years since the initial treatment. As seen in this case, favorable prognosis can be achieved even for stage IVB advanced uterine cervical cancer patients, when the distant metastases are located in lymph nodes where CCRT could fully cover.

Background Standard chemoradiotherapy (CRT) using 5-FU and CDDP is the optimal treatment for patients with stage II/III (non-T4) esophageal carcinoma. However, patient quality of life (QOL) cannot necessarily be maintained during this therapy, because 5-FU must be continuously infused for 24 h and CDDP administration requires a large transfusion volume. Therefore, hospitalization is unavoidable. We conducted a study of definitive CRT with S-1 and nedaplatin.

Although radical hysterectomy is the standard surgical treatment for patients with stage IB and II cervical cancer, it does not improve the prognosis of high-risk patients even if postoperative radiotherapy is added. There is therefore a need to establish some other therapeutic regimen. In the present retrospective study, the efficacy of concurrent nedaplatin after radical hysterectomy in high-risk stage IB to II cervical cancer was analyzed. From 1995 through 2005, patients with an International Federation of Gynecology and Obstetrics stage of IB2 and II cervical cancer who were given only radiotherapy (RT; n = 17) or postoperative concurrent chemoradiotherapy with biweekly nedaplatin at 70 mg/m(2) (p-CCRT; n = 13) were entered. All of the patients had at least one of the following risk factors: lymphovascular space infiltration, positive lymph nodes, or parametrial invasion. There was no significant difference between the RT and p-CCRT groups with regard to mean age and risk factors, except that more patients in the p-CCRT group had positive lymph nodes (P < 0.05). Five-year progression-free survival and overall survival after RT versus p-CCRT were 76.0% versus 83.3%, and 81.9% versus 83.3%, respectively. Although many patients in the p-CCRT group had positive lymph nodes, there was no significant difference in either PFS or OS. No grade 4 myelosuppression or other severe side effects were seen in the p-CCRT group. As CCRT with nedaplatin might have some benefit, a randomized control trial should be conducted in the future.

The breast and ovarian tumor suppressor BRCA1 constitutes a RING heterodimer E3 ligase with BARD1. BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that bound to the RING finger domain of BRCA1. However, how BAP1 contributes to the E3 activity of BRCA1/BARD1 is unclear. Here, we report that BAP1 interacts with BARD1 to inhibit the E3 ligase activity of BRCA1/BARD1. Domains comprised by residues 182-365 of BAP1 interact with the RING finger domain of BARD1, and surface plasmon resonance spectroscopy (BIAcore) analyses showed that BAP1 interferes with the BRCA1/BARD1 association. The perturbation resulted in inhibition of BRCA1 autoubiquitination and NPM1/B23 ubiquitination by BRCA1/BARD1. Although BAP1 was capable of deubiquitinating the polyubiquitin chains mediated by BRCA1/BARD1 in vitro, a catalytically inactive mutant of BAP1, C91S, still inhibited the ubiquitination in vitro and in vivo, implicating a second mechanism of action. Importantly, inhibition of BAP1 expression by short hairpin RNA resulted in hypersensitivity of the cells to ionizing irradiation and in retardation of S-phase progression. Together, these results suggest that BAP1 and BRCA1/BARD1 coordinately regulate ubiquitination during the DNA damage response and the cell cycle. [Cancer Res 2009;69(1):111–9]