Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Unusual visual and olfactory perceptions during radiotherapy sessions: an investigation of the organs responsible.

During radiotherapy sessions to treat brain tumors or head-and-neck cancers, some patients experience unusual visual and/or olfactory perceptions. This prospective study sought to answer two questions: (i) what proportion of patients experience these unpleasant sensations?, and (ii) which organs are responsible? Eligible patients had brain or near-orbital tumors treated by helical tomotherapy. All were aged 10 years or older, able to communicate, and interviewed by a radiation oncologist at least once weekly during radiation therapy. If they had experienced such sensations, they were encouraged to join the second phase of the study. The patients were asked to indicate, using a button, when a sensation commenced and ended. The recorded data were collated with the treatment log. Thirty-eight consecutive patients were eligible. Twenty-six experienced visual and 13 olfactory sensations. The radiation doses to the organs related to the visual or olfactory sensations did not differ between patients who reported sensations and those who did not. Seventeen patients were enrolled in the second phase of the study. All 14 with visual sensations reported that the sensations occurred when the X-rays passed at eye level. Olfactory sensations were reported by eight out of nine patients when the X-rays passed through the olfactory epithelium and/or ethmoid sinus level. In conclusion, 68% of patients experienced visual sensations caused by X-rays passing through the level of the eyes, and 34% complained of olfactory sensations. With the exception of one patient, olfactory sensations occurred when the X-rays passed through the levels of the olfactory epithelium and/or ethmoid sinus.

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701).

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.

Alternating chemoradiotherapy for nasopharyngeal cancer using cisplatin and 5-fluorouracil: a preliminary report of phase II study.

Alternating chemoradiotherapy was performed in 35 patients with locally advanced nasopharyngeal cancer. The median duration of follow-up was 20 months, and the 2-year progression free and overall survival rates were 83% (95% confidence interval: 66~101%) and 94% (95% CI: 84~105%), respectively. This method may be useful in treating nasopharyngeal cancer.

Localized aggressive non-Hodgkin's lymphoma of the nasal cavity: a survey by the Japan Lymphoma Radiation Therapy Group.

PURPOSE: To clarify the role of radiotherapy and chemotherapy in the treatment of patients with localized aggressive non-Hodgkin's lymphomas (NHL) originating in the nasal cavity. METHODS AND MATERIALS: The survey, administered at 25 Japanese institutes in 1998, enabled us to collect the clinical data for 787 patients with localized aggressive NHL who were treated between 1988 and 1992. RESULTS: There were 42 patients (5%) with nasal lymphomas. Twelve of these patients received radiotherapy alone, and 30 were treated with a combination of radiotherapy and chemotherapy. The median radiation dose was 47 Gy (22-66). Twelve patients were reviewed histopathologically according to REAL (Revised European-American Classification of Lymphoid neoplasms) classification. T-cell or natural killer (NK) cell lymphomas were detected in 9 patients (75%), and diffuse large B-cell lymphomas in 3 (25%). The 5-year overall and disease-free survival (DFS) rates of all patients were 57% and 59%, respectively. The 5-year DFS rate for the 30 patients treated with the combined therapy was 64% and that for the 12 patients treated with radiotherapy alone was 46% (p = 0.021). For the 34 patients with stage-modified International Prognostic Index (m-IPI) 0-1, the 5-year DFS rates of those treated with the combined therapy and radiotherapy alone were 68% and 45%, respectively (p = 0.020), but there was no difference in DFS rate among the two groups of patients with m-IPI 2-3. The 5-year local control rates of the patients who received >46 Gy (n = 22) and < or =46 Gy (n = 20) were 95% and 76% (p = 0.087), respectively. There was no significant difference among the 5-year DFS rates (62% vs. 67%) and local control rates (87% vs. 100%) of the patients with T-cell or NK-cell lymphoma and diffuse large B-cell lymphoma. CONCLUSIONS: Patients with nasal lymphomas (m-IPI 0-1) should be treated with combined therapy. For the patients with high risk (m-IPI 2-3), the effectiveness of combined therapy was not clarified because of the small number of the patients. A high radiation dose >46 Gy may need to be used to achieve good local control.

A case of POEMS syndrome with high concentrations of interleukin-6 in pericardial fluid.

The POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy of various forms, monoclonal gammopathy, skin changes) is a rare multisystem disorder of unknown pathogenesis. Overexpression of proinflammatory cytokines has been implicated in the pathogenesis of POEMS syndrome, however, it is not known whether there is an association between abnormalities in cytokines and pericardial fluid. We present a case of POEMS syndrome with high concentrations of interleukin-6 (IL-6) in pericardial fluid. In our patient, pericarditis developed into cardiac tamponade, and the concentration of IL-6 in pericardial fluid was remarkably elevated compared with that in serum (1760 vs. 6.57 pg mL(-1)). We suggest that IL-6 is associated with the progression or maintenance of pericarditis as a result of POEMS syndrome.

Evaluation of central nervous system involvement in nasal lymphomas.

OBJECTIVES: To clarify the usefulness of evaluating central nervous system (CNS) involvement in patients with nasal lymphomas at the initial staging procedure, and of CNS prophylaxis for patients with clinical stage I/II. PATIENTS AND METHODS: We retrospectively reviewed 43 patients with nasal lymphomas who had been treated from 1973 through 1999. The staging procedure included mainly computed tomography (CT), ultrasonography, gallium scintigraphy, upper gastrointestinal study, magnetic resonance (MR) imaging, and bone marrow biopsy. Forty-two patients received radiotherapy, and 25 patients received chemotherapy. All 38 patients with stage I/II were not subjected to CNS prophylaxis. RESULTS: Four patients demonstrated CNS involvement at the staging procedure. MR imaging demonstrated the tumor had directly infiltrated the skull base in 3 patients, but CT demonstrated CNS infiltration in only one patient. In another patient, cerebrospinal fluid (CSF) cytologic analyses demonstrated CNS involvement, but MR imaging and CT did not. These 4 patients complained of frontonasal pain and/or cerebral nerve dysfunction. No patient with stage I/II developed CNS relapse. CONCLUSIONS: MR imaging and CSF cytologic analyses should be performed at the initial staging of nasal lymphomas, especially in patients with frontonasal pain and/or cerebral nerve dysfunction. Patients with stage I/II might not need CNS prophylaxis.

Fulminant Mycoplasma pneumoniae pneumonia.

A 64-year-old woman, who was previously in good health was admitted because of progressive respiratory distress. Her chest radiograph revealed bilateral widespread alveolar infiltrates. She was given a diagnosis of pneumonia caused by Mycoplasma pneumoniae serologically, acute respiratory distress syndrome, and disseminated intravascular coagulation. She died of multiple organ failure despite intensive therapy with mechanical ventilation, intravenous erythromycin and corticosteroids, continuous hemodiafiltration, and plasma exchange. Although Mycoplasma pneumoniae infection is usually a benign self-limited disease, this case emphasizes its potentially serious nature even in normal healthy individuals.

Coronary flow reserve in angiographically normal coronary arteries with one-vessel coronary artery disease without traditional risk factors.

AIMS: Reduced coronary flow reserve has been reported in patients with traditional risk factors, in particular hyperlipidaemia, despite angiographically normal coronary arteries. However, it is recognized that traditional risk factors do not explain the presence of coronary atherosclerosis in a large proportion of patients. The aim of this study was to assess whether coronary flow reserve is preserved in the myocardium supplied by normal coronary arteries in patients with one-vessel coronary artery disease without traditional risk factors. METHODS AND RESULTS: Positron emission tomography using [13N]ammonia was performed at baseline and after intravenous dipyridamole administration (0.56 mg x dl(-1)over 4 min) in 30 subjects: six patients with ischaemia on effort, no myocardial infarction, and isolated left anterior descending coronary artery stenosis without traditional risk factors (coronary artery disease patients without risk factors, aged 59+/-13), five patients with ischaemia on effort, no myocardial infarction, and isolated left anterior descending coronary artery stenosis with multiple risk factors (coronary artery disease patients with risk factors, aged 69+/-7), 11 age-matched controls (aged 58+/-6), and eight healthy young volunteers (aged 34+/-4). Myocardial blood flow calculated in the myocardium supplied by normal coronary arteries in the coronary artery disease patients was compared with those of the two control groups. Coronary flow reserve was defined as the ratio of hyperaemic blood flow after dipyridamole infusion to baseline blood flow. Although coronary flow reserve in the coronary artery disease patients with risk factors was significantly lower than that in the age-matched controls (1.62+/-0.37, 2.58+/-0.71, P=0.0428), coronary flow reserve in the coronary artery disease patients without risk factors was similar to that in the age-matched controls (2.54+/-0.17 vs 2.58+/-0.71, P=ns). CONCLUSION: Coronary flow reserve is preserved in regions supplied by angiographically normal coronary arteries with one-vessel coronary artery disease without traditional risk factors.

Ulcer in the gastric tube for esophageal replacement: a comparison of 12 esophageal cancer patients with or without postoperative radiotherapy.

BACKGROUND AND AIMS: Ulcer in the gastric tube for esophageal replacement, which was caused by peptic factors or postoperative radiotherapy (Rx), are occasionally reported. The aim of this study was to clarify the clinicopathologic features of the ulcers in the gastric tube. METHODS: In 62 patients with a reconstructed gastric tube, after esophagectomy for esophageal cancer, esophagogastroduodenoscopy was performed. Ulcers of the gastric tube were detected in 12 patients: six with postoperative Rx and six without Rx. The 12 patients with gastric tube ulcers (GU-group) were reviewed and compared to the remaining 50 patients without ulcers of the gastric tube (Control-group). Clinicopathologic features of gastric tube ulcers were compared between the patients with and without Rx. RESULTS: There was no difference in any parameter between the patients of the GU- and Control-groups. Comparing the patients of the GU-group with and without Rx, the ulcers of the gastric tube in the patients without Rx were frequently located in the lower part of the gastric tube (P = 0.067), detected in a later period after surgery (P = 0.055), associated with cervical esophagitis (P = 0.03), and less associated with gastritis (P = 0.03). In three patients of the GU-group without Rx, Helicobacter pylori was detected in the gastric tube. Two of the three patients had a history of peptic ulcers before surgery, and had recurrence of the gastric tube ulcers. CONCLUSIONS: Gastric tube ulcers without postoperative Rx may have different characteristics compared to those induced by Rx.

Control of gene expression and the cell cycle.

The pRb tumour suppressor protein is an essential component of the cell-cycle clock, integrating both positive and negative signals for cellular growth and proliferation with the transcription machinery. pRb exerts its tumour suppression function by both antagonizing and synergizing with downstream effectors, such as E2F. pRb has two modes of action, it can inactivate E2F transcription activity or it can assemble an active repression complex with E2F. Apart from E2F, pRb interacts with various factors to promote cellular differentiation. The differentiation properties of pRb are likely to contribute partly to its tumour suppressor function. It is also clear that pRb is a master regulator for transcription. It can both activate and repress transcription in a context-dependent manner. pRb interacts directly with histone acetyltransferase, histone deacetylases and SWI/SNF proteins, all of which are classes of proteins involved in chromatin remodelling. Last, but not least, pRb regulates transcription driven by all three polymerases, thereby integrating the cell-cycle clock with the biosynthetic capacity of the cell in controlling cellular proliferation and growth.

Functional interaction between nucleosome assembly proteins and p300/CREB-binding protein family coactivators.

The p300/CREB-binding protein (CBP) family of proteins consists of coactivators that influence the activity of a wide variety of transcription factors. Although the mechanisms that allow p300/CBP proteins to achieve transcriptional control are not clear, it is believed that the regulation of chromatin is an important aspect of the process. Here, we describe a new level of p300-dependent control mediated through the functional interaction between p300/CBP and members of the family of nucleosome assembly proteins (NAP), which includes NAP1, NAP2, and TAF1. We find that NAP proteins, which have previously been implicated in the regulation of transcription factor binding to chromatin, augment the activity of different p300 targets, including p53 and E2F, through a process that is likely to involve the physical interaction between p300 and NAP. NAP proteins can form oligomers, and the results show that NAP proteins can bind to both core histones and p300 coactivator proteins, perhaps in a multicomponent ternary complex. We also provide data in support of the idea that histones can influence the interaction between p300 and NAP protein. These results argue that NAP is a functionally important component of the p300 coactivator complex and suggest that NAP may serve as a point of integration between transcriptional coactivators and chromatin.

A case of rheumatoid pericarditis with high concentrations of interleukin-6 in pericardial fluid.

A case of rheumatoid pericarditis that developed into cardiac tamponade without deterioration of rheumatoid arthritis is described. The concentration of interleukin-6 (IL-6) in pericardial fluid was notably increased compared with serum. IL-6 may be associated with progression or maintenance of rheumatoid pericarditis.

[Non-randomized study on the effects of preoperative radiotherapy and daily administration of low-dose cisplatin against those of radiotherapy alone for oral cancer--effects on local control, control of metastases, and overall survival].

Cisplatin is a known radiation modifier. Our previous study suggested that daily administration of low-dose cisplatin enhanced the efficacy of radiotherapy against primary oral squamous carcinoma. In this paper, we follow the patients who participated in the previous study and survey the benefit of combination low-dose cisplatin in improving local control, prevention of metastases, and overall survival. This study included patients with surgically resectable advanced oral tumors. Ten patients underwent preoperative radiotherapy of 30-40 Gy/15-20 days with concomitant daily administration of low-dose cisplatin (5 mg/body or 5 mg/m2). Ten other patients received external radiotherapy alone. All patients then underwent a planned radical tumor resection. No significant difference was see in loco-regional control rates (primary: 86 vs. 88%, neck: 83 vs. 78% at 48 months) or incidence of metastasis (70 vs. 64%) between the two groups. Nor was there a significant difference in the overall survival rate (60 vs. 66%). The results of this study suggest that the concomitant use of daily administration of low-dose cisplatin with preoperative radiation brings no statistically significant benefit in improving local control and survival rate in patients with advanced resectable oral cancer.

A novel cofactor for p300 that regulates the p53 response.

The ability of p53 to function as a transcription factor is instrumental in facilitating the response to cellular stress, and p300/CBP proteins, which act as coactivators for diverse transcription factors, participate in regulating p53 activity. We report a novel cofactor for p300 that facilitates the p53 response by augmenting p53-dependent transcription and apoptosis. JMY and p300 associate in physiological conditions, and, during the cellular stress response, the p300/JMY complex is recruited to activated p53. The bax gene is efficiently activated by JMY, and protein isoforms that arise through alternative splicing alter the functional outcome of the p53 response. The results provide compelling evidence that the p300/JMY coactivator complex plays a central role in facilitating the p53 response.

Prognostic utility of myocardial blood flow assessed by N-13 ammonia positron emission tomography in patients with idiopathic dilated cardiomyopathy.

Previous studies in patients with idiopathic dilated cardiomyopathy (IDC) have suggested that myocardial perfusion is impaired and spatially heterogeneous in such cases. Our objective was to identify any association between an abnormality in myocardial perfusion and the prognosis of patients with IDC. We collected data on N-13 ammonia positron emission tomography (PET) studies performed in 26 patients with IDC (9 nonsurvivors, 17 survivors) and in 8 normal control subjects. Regional myocardial blood flow (rMBF) was quantified using N-13 ammonia positron emission tomography and the Simple flow model. The spatial heterogeneity of myocardial perfusion was assessed by calculating the coefficient of variance of rMBF. Mean rMBF of the survivors was significantly lower (0.54 +/- 0.13 ml/min/g) than that of control subjects (0.66 +/- 0.06 ml/min/g) (p = 0.03 vs control), but did not differ significantly between nonsurvivors (0.58 +/- 0.15 ml/min/g) and control subjects. The coefficient of variance of rMBF was significantly higher in nonsurvivors than in either survivors or control subjects (0.24 +/- 0.08 vs 0.15 +/- 0.08, p = 0.007, and 0.16 +/- 0.05, p = 0.03, respectively). The probability of 3-year survival (Kaplan-Meier method) was 33.0% in subjects whose coefficient of variance of rMBF was above the median compared with 90.0% in subjects whose coefficient of variance of rMBF was below the median (p = 0.01). The probability of 3-year survival did not differ among subjects whose mean rMBF was above versus below the median (61.5% vs 62.9%, respectively). The results suggest that the prognosis of patients with IDC is associated with the spatial heterogeneity of myocardial perfusion, not with initial absolute rMBF.

Radiotherapy following mastectomy: indication and contraindication of chest wall irradiation.

PURPOSE: To determine in which cases radiotherapy of the chest wall following mastectomy is indicated, based on the local recurrent rate in patients with locally advanced breast cancer. METHODS AND MATERIALS: From 1984 until 1994, 105 patients who had four or more histopathologically confirmed axillary nodes metastases, or T3-4Nany, were subjected to mastectomy and were administered radiotherapy postoperatively using the hockey-stick field, which included the ipsilateral supraclavicular fossa and internal mammary nodes, except the chest wall. Median age was 51 years old (range, 23 to 82 years old). Eighty-five patients underwent radical mastectomy, 18 modified radical mastectomy, and 2 extended radical mastectomy. Fraction size was 2 Gy/day, the weekly fraction size was 10 Gy and the total dose ranged from 44 Gy to 54 Gy (median 50 Gy). Seventy-four patients were administered adjuvant chemotherapy, and 61 patients were administered hormone therapy. RESULTS: The 5-year disease-free survival rates of the whole study population were 66%. The 5-year chest wall recurrence rates were 10%. The 5-year chest wall recurrence rates of the patients who had no vascular invasion (n = 19) and the patients who had definite vascular invasion (n = 38) were 0% and 24%, respectively (p = 0.036). All the patients who presented chest wall recurrence had four or more axillary nodes metastases. Nine of the 10 patients who presented chest wall recurrence had definite vascular invasion, while there was no information about vascular invasion for the remaining patient. Factors such as age, pathological subtypes, tumor location, estrogen receptors, extent of resection, chemotherapy, and hormone therapy did not influence the development of chest wall recurrence. CONCLUSION: Among patients with breast cancer who have four or more positive axillary nodes or T3-4Nany, those who have no vascular invasion or less than 4 axillary nodes metastases do not need to be subjected to chest wall irradiation after radical mastectomy.

Functional interplay between p53 and E2F through co-activator p300.

Both E2F and p53 are sequence specific transcription factors that regulate early cell cycle progression. The pathway of control mediated through E2F governs the transition from G1 into S phase whereas p53 in response to genotoxic stress can facilitate cell cycle arrest or apoptosis. The mechanisms which influence the outcome of p53 induction are not clear, although transcription of the p53 target gene, encoding the cdk-inhibitor p21(Waf1/Cip1), correlates with p53-mediated cell cycle arrest. Here using a combination of biochemical and functional assays we identify p300 as a co-activator required for p53-dependent transcriptional activation of Waf1/Cip1. Furthermore, we show that the cdk-inhibitor p21(Waf1/Cip1) autoregulates in a positive fashion transcription through modulating the activity of the p53/p300 complex, whilst negatively regulating the activity of E2F by preventing cdk-dependent phosphorylation of pRb. Consistent with a role for p21(Waf1/Cip1) in the autoregulation of p53-dependent transcription, p300 augments the ability of p53 to cause G1 arrest and, conversely, cells undergoing p53-dependent apoptosis are rescued by p300. Thus, our data suggest that the ability of p300 to interact with p53 influences the physiological consequence of p53 activation. From previous studies it is known that cells expressing aberrant levels of E2F-1 can undergo p53-dependent apoptosis. In addition, we find that E2F-1 can cause apoptosis in p53-/- tumour cells and further p300, which also functions as a co-activator for the E2F/DP heterodimer, enhances the apoptotic activity of E2F-1. In conditions where E2F-1 and p53 co-operate in apoptosis E2F-1 can effectively compete for p300, causing a reduction in p53-dependent transcription. Thus, a functional interaction between p300 and either p53 or E2F-1 has a profound impact on early cell cycle progression, specifically in regulating the contrasting outcomes of cell cycle arrest and apoptosis. These results suggest a critical role for p300 in integrating and co-ordinating the functional interplay between the pathways of growth control mediated by E2F and p53.