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Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology - RSS feed of current issue

Brain metastases are less common than bone or visceral metastases in patients with breast cancer. The overall prognosis of breast cancer patients with brain metastases remains poor, and these metastases are less responsive to systemic therapies. Brain metastasis is associated with a reduced quality of life due to progressive neurologic impairments. Recently, a trend of increased incidence of brain metastases in breast cancer has been noted. Reasons for this increased incidence include the more frequent use of sensitive detection methods such as contrast-enhanced magnetic resonance imaging and increased awareness of brain metastasis among patients and clinicians. Adjuvant and systemic therapy with drugs that have a low blood–brain barrier penetrance can lead to an increased risk of brain metastases in breast cancer patients. Molecular subtype is a predictive factor for overall survival after developing brain metastases. Patients who do not have a poor prognosis based on previously identified prognostic factors should be treated with radiation therapy to control symptoms. Whole-brain radiation therapy, stereotactic irradiation and surgery are tools for the local treatment of brain metastases. Novel molecular target therapy, including HER2-targeted therapy, has demonstrated an antitumor effect on brain metastases. In this review, we provide a practical algorithm for the treatment of breast cancer brain metastases. This review provides an overview of the incidence, risk factors, diagnosis, prognostic factors and current and potential future management strategies of breast cancer brain metastases.


Stem cells of the digestive system are ideal in many ways for research, given they are abundant, highly proliferative and have a uniform structural arrangement. This in turn has enormously aided the research of cancer stem cells of the digestive system, which is now shaping our understanding of cancer stem cells. In this review, the recent advances in the understanding of cancer stem cells of the digestive system have been summarized, including aspects such as their identification, origin, cell-cycle dormancy, relationship with epithelial–mesenchymal transition, cellular metabolism and the underlying molecular mechanisms. Newly acquired knowledge concerning cancer stem cells have led to the development of novel cancer therapeutics with provisional yet encouraging results.


Objective

Quality of life after diagnosis and during treatment phases of breast cancer varies across individual to individual, country to country and from ethnicity to ethnicity. So factors affecting it are of growing research interest. The aim of the study was to investigate the influence of socioeconomic status and body mass index on the quality of life of breast cancer patients during the phases of treatment-before and after mastectomy.

Methods

Two hundred and fifty-one women with breast cancer undergoing surgery were interviewed prior to and after mastectomy in National Institute of Cancer Research and Hospital, Dhaka from January 2012 to March 2013 using European Organization for Research and Treatment of Cancer Core Questionnaire (and QLQ-Br23). Socioeconomic factors like educational status, family income, occupation and body mass index were taken as investigating factors against global health status and breast cancer-related factors.

Results

Significant reduction of the scores found that means deterioration of function in the following domains of the quality of life were found such as physical well-being (P = 0.019), emotional well-being (P = 0.035), cognitive status (P = 0.05) and the breast-specific subscales like BRBI (body image), BRBS (breast symptoms), BRAS (arm symptoms); (P = 0.013, 0.103, 0.015) was observed after surgery in lower income group. Worker group expressed also similar effect on the global health status/quality-of-life scales (P = 0.05, 0.043, 0.021) and breast subscales (P = 0.002, 0.027, 0.05), patients with lower body mass index also have a lower score also. Educational status does not affect the two groups. Younger age group patients expressed much distress.

Conclusions

Improvement of family income, nutritional status and improvement of working environment might have an impact on the improvement of the quality of life of breast cancer patients during the phases of treatment.


Objective

The goals of treatment for head and neck cancer are cure and organ-function preservation. For organ preservation, primary treatment via radiotherapy alone is thought to be insufficient for Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx. The objective of the present study was to investigate the efficacy and safety of concurrent chemoradiotherapy with S-1 for patients with Stage II squamous cell carcinoma of the pharynx or larynx for primary organ preservation.

Methods

Previously untreated patients with Stage II squamous cell carcinoma of the larynx, oropharynx or hypopharynx received three courses of S-1 (40 or 50 mg twice a day; 2 weeks of administration followed by 1 week of rest every 3 weeks) during conventional radiotherapy (a single daily fraction of 1.8 Gy) to a total dose of 70.2 Gy. The primary endpoint was the local control rate at 3 years.

Results

From August 2009 to October 2012, 37 patients were evaluated for the study. The overall response rate was 100%. The 3-year local control rate was 89.0% (95% confidence interval, 78.9–99.2%), and the 3-year overall survival rate was 97.2% (95% confidence interval, 91.8–100%). Mucositis and dermatitis in the radiation field were the most common acute adverse events observed. The rates of Grade 3 mucositis and dermatitis were 27 and 35%, respectively. No patients experienced Grade 4 acute adverse events. The treatment completion rate was 89.2%.

Conclusion

Concurrent chemoradiotherapy with S-1 was safe and effective in improving local control for Stage II squamous cell carcinoma of the pharynx or larynx.


Objective

Epstein–Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities.

Methods

To define the clinical characteristics as well as the prognostic impact of Epstein–Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein–Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute.

Results

Using a cutoff point of positive nuclear staining of Epstein–Barr virus-encoded RNA-1-in situ hybridization in ≥20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein–Barr virus-positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein–Barr virus-positive and -negative diffuse large B-cell lymphoma patients. Univariate analysis showed patients with diffuse large B-cell lymphoma that were either Epstein–Barr virus-positive or had activated B-cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein–Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor.

Conclusions

Taken together, we demonstrated that a higher frequency of Epstein–Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein–Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients.


Objective

We report the response to pre-operative gemcitabine-based chemoradiotherapy for pancreatic adenocarcinoma.

Methods

Thirty-five consecutive patients with borderline resectable pancreatic adenocarcinoma of UICC Stage II or III with portal vein invasion or tumor abutment of artery received radiotherapy (twice daily fractions of 1.5 Gy, 5 days/week, total dose: 36 Gy; 30 Gy for Phase I Level 1) with weekly intravenous infusions of gemcitabine (400, 600 and 800 mg/m2) at Days 1 and 8 for Phase I and 800 mg/m2 for Phase II. Restaging was repeated after completion of chemoradiotherapy.

Results

Twenty-six of the 35 (74.3%) patients underwent resection. The dose-limiting toxicities were Grade 4 neutropenia and thrombocytopenia. The recommended regimen was total radiation dose of 36 Gy with gemcitabine 800 mg/m2. Surgical resection was conducted in 11 of the 15 (73.3%) patients in Phase I study and 15 of the 20 (75.0%) in Phase II. After recommended dose chemoradiotherapy and surgical resection, the median disease-free survival was 17.4 months (5-year survival rate = 14.3%). The median overall survival time and 5-year survival rate were 41.2 months and 28.6%, respectively, for the 21 patients who underwent resection and 10.0 months and 0%, respectively, for those 5 who did not (P = 0.004).

Conclusion

Our pre-operative gemcitabine-based chemoradiotherapy was well tolerated and safe.


Objective

The primary endpoints of this study were: (1) to explore the distressing experiences of parents of patients with intractable pediatric cancer in Japan from disclosure of poor prognosis to the present and (2) to explore support they regarded as necessary.

Methods

A multi-center questionnaire survey was conducted that included 135 bereaved parents of patients with pediatric cancer in Japan.

Results

The top five distressing experiences shared by over half of the bereaved parents were: ‘Realize that the child's disease was getting worse’ (96.7%), ‘Witness the child's suffering’ (96.7%), ‘Make many decisions on the basis that the child will die in the not-so-distant future’ (83.6%), ‘Feel anxious and nervous about the child's acute deterioration’ (82.0%) and ‘Realize that there was nothing that I could do for the child’ (78.7%). The top five support regarded as necessary were: ‘Visit the room and speak to the sick child every day’ (90.2%), ‘Provide up-to-date information’ (80.3%), ‘Sufficiently explain the disadvantages of each treatment option’ (80.3%), ‘Show a never-give-up attitude until the end’ (78.7%) and ‘Make arrangements to allow the sick child to spend time with his/her siblings’ (73.8%).

Conclusions

This study identified the common distressing experiences of parents and the support regarded as necessary by them. To provide efficient support with limited manpower in pediatric setting, healthcare professionals should recognize these tasks as high priorities when engage parents of intractable pediatric cancer patients.


Objective

Pain control helps improve quality of life for advanced cancer patients, yet it is unknown whether opioid use increases risk of death. Analyzing the association between time-varying pain medication and the risk of death presents a challenge. This prospective observational study examined the predictability of the patients' survival by variations of daily opioid dosage during the last few days of life.

Methods

Of the 231 cancer patients admitted to a hospice ward between July 2007 and June 2008 was conducted using Cox's model and adjusting for the effects of demography, clinical symptoms/signs, intravenous fluid supplements, antibiotics use and laboratory tests.

Results

We found a 3-day negative slope in daily oral morphine equivalent 1 day before each death event to be an independently significant predictor of short time to death (hazard ratio = 1.55; 95% confidence interval: 1.06–2.27). The other significant predictors including faster heart-rate (hazard ratio = 1.01, 95% confidence interval: 1.00–1.02), comorbidity with diabetes (hazard ratio = 1.57, 95% confidence interval: 1.00–2.47), Eastern Cooperative Oncology Group with performance status of 3 or 4 (hazard ratio = 1.78, 95% confidence interval: 1.23–2.58), jaundice (hazard ratio = 2.01, 95% confidence interval: 1.29–3.15), hypercalcemia (hazard ratio = 2.05, 95% confidence interval: 1.40–3.00) and higher serum creatinine level (hazard ratio = 1.36, 95% confidence interval: 1.18–1.57), but use first generation of cephalosporin was a negative predictor of short time to death (hazard ratio = 0.44, 95% confidence interval: 0.28–0.68).

Conclusion

A reduction of daily oral morphine equivalent over three consecutive days suggests worsening physical condition significantly and independently predicting imminent death ~1 day later.


Objective

The purpose of this study was to evaluate the diagnostic utility of lung-specific X protein (LUNX) mRNA and vascular endothelial growth factor mRNA in differentiating pleural effusion of different origin.

Methods

A total of 136 patients with pleural effusion (46 cases of malignant pleural effusion caused by lung cancer, 30 cases of malignant pleural effusion caused by other cancers and 60 cases of benign pleural effusion) were enrolled in this study. Levels of LUNX mRNA and vascular endothelial growth factor mRNA in pleural fluid were detected by real-time quantitative polymerase chain reaction. Pleural fluid carcinoembryonic antigen and Cyfra21-1 were also measured simultaneously.

Results

The LUNX mRNA level was significantly higher in malignant pleural effusion caused by lung cancer than in malignant pleural effusion caused by other cancers and in benign pleural effusion. In malignant pleural effusion caused by cancers of different origin, the vascular endothelial growth factor mRNA level was significantly higher than in benign pleural effusion. For the diagnosis of malignant pleural effusion caused by lung cancer, LUNX mRNA exhibited higher sensitivity (80%), when compared with vascular endothelial growth factor mRNA (65%), carcinoembryonic antigen (67%) and Cyfra21-1 (61%), with the same specificity (95%). The combination of LUNX mRNA and cytology achieved a sensitivity of 85%. The combined use of LUNX mRNA and vascular endothelial growth factor mRNA and cytology raised the sensitivity to 89%, with 95% specificity. In initial cytology-negative pleural effusion from lung cancer, LUNX mRNA achieved the highest positive result (65%) among the four markers.

Conclusions

The detection of LUNX mRNA and vascular endothelial growth factor mRNA in pleural fluid may be a complementary tool for the diagnosis of malignant pleural effusion. In particular, pleural fluid LUNX mRNA provided a valuable adjunct in distinguishing malignant pleural effusion caused by lung cancer from benign pleural effusion.


Objective

In this Phase 2 multicenter study the efficacy and safety of oral abiraterone acetate (1000 mg/once daily) plus prednisolone (5 mg/twice daily) was evaluated in metastatic castration-resistant prostate cancer patients from Japan who had previously received docetaxel-based chemotherapy.

Methods

Men (aged ≥20 years) with metastatic castration-resistant prostate cancer (prostate-specific antigen levels: ≥5 ng/ml), who had received 1 or 2 cytotoxic chemotherapies (with ≥1 regimen being docetaxel) for prostate cancer, were enrolled in this open-label, single-arm study. Primary efficacy endpoint was proportion of patients achieving a ≥50% prostate-specific antigen decline from baseline (prostate-specific antigen response rate) after 12-week treatment. Safety and pharmacokinetics were also assessed.

Results

Confirmed prostate-specific antigen response rate by Week 12 was 28.3% (90% confidence interval: 17.6%; 41.1%) or 13 out of 46 (full analysis set) treated patients. However, total prostate-specific antigen response rate including confirmed and unconfirmed responses was 34.8% (90% confidence interval: 23.2%; 47.9%). Secondary efficacy endpoints and outcomes were: improvement in Eastern Cooperative Oncology Group performance status score by ≥1 unit: 7/16 patients (43.8%); objective radiographic response: complete response, partial response and stable disease in 0, 1/22 (4.5%) and 9/22 (40.9%) patients, respectively; pain palliation response: 9/16 (56.3%) patients. The most common adverse events (>20% patients) were upper respiratory tract infection (13/47, 27.7% patients) and hepatic function abnormal (10/47, 21.3% patients, Grade 3: 8.5%). All mineralocorticoid-related toxicities were Grade 1/2.

Conclusions

Abiraterone acetate plus prednisolone showed favorable efficacy in metastatic castration-resistant prostate cancer Japanese patients who had received chemotherapy. Abiraterone acetate plus prednisolone had an acceptable safety profile.

Clinical trial registration no

NCT01795703.


Objective

Abiraterone acetate has been approved in >70 countries for chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naïve Japanese patients with metastatic castration-resistant prostate cancer was evaluated.

Methods

Men, ≥20 years, with prostate-specific antigen levels of ≥5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of ≥50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed.

Results

A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: –66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2.

Conclusions

Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile.

Clinical trial registration no

NCT01756638.


Objective

To investigate survival of hormone-naïve prostate cancer patients diagnosed with prostate-specific antigen ≥500 ng/ml, stratified according to the prostate-specific antigen level and type of therapy.

Methods

Data of prostate cancer patients with prostate-specific antigen ≥500 ng/ml diagnosed between 2001 and 2003 and receiving primary androgen deprivation therapy were extracted from the Japan Study Group of Prostate Cancer database. Cancer-specific survival and overall survival were assessed according to the prostate-specific antigen level (500–999, 1000–4999 and ≥5000 ng/ml) and type of therapy using Kaplan–Meier analyses and multivariate Cox proportional hazards models including age, Gleason score, oncological stage and comorbidity.

Results

The median follow-up was 27 months (interquartile range, 13–51) and a total of 1961 patients were included. Five-year cancer-specific and overall mortalities were 39.0 and 33.0%, respectively. There was a significant inverse relationship between overall survival and prostate-specific antigen magnitude among combination therapy patients, but not monotherapy patients (log-rank test, P = 0.034 and 0.558, respectively). The median overall survival in combination therapy patients with low-, intermediate- and high prostate-specific antigen and monotherapy patients with any prostate-specific antigen were 79, 59, 45 and 43 months, respectively. Multivariate analysis showed that combination therapy in patients with low- and intermediate prostate-specific antigen was significantly associated with a favorable overall survival compared with monotherapy (hazard ratios 0.66 and 0.75, respectively, both P < 0.001). Similar results were obtained for cancer-specific survival.

Conclusions

There are major survival differences in extremely high prostate-specific antigen cases according to the prostate-specific antigen level and hormone therapy type and those patients would benefit notably from combination androgen blockade.


Objective

It remains unclear whether lymphadenectomy alters regional node recurrence after nephroureterectomy in patients with urothelial carcinoma of the renal pelvis. The predictive factors for regional node recurrence are still unclear. In this study, we retrospectively examined how the extent of lymphadenectomy influences regional node recurrence in patients with urothelial carcinoma of the renal pelvis.

Methods

From January 1988 through July 2013, we performed nephroureterectomy in 180 patients with non-metastatic (cN0M0) urothelial carcinoma of the renal pelvis at two Japanese institutes. Regional nodes were determined according to our previous mapping study: complete lymphadenectomy designates that all regional sites were dissected; incomplete lymphadenectomy that all sites were not dissected. A third group included those without lymphadenectomy.

Results

The 5-year cancer-specific and recurrence-free survival was significantly higher in the complete lymphadenectomy group than in the incomplete lymphadenectomy or without lymphadenectomy groups (P = 0.03). The incidence of regional node recurrence was significantly lower in the complete lymphadenectomy group at 2.9% (2/67) than in the incomplete lymphadenectomy at 18.1% (4/22) or without lymphadenectomy at 10.9% (10/91) groups (P = 0.03). In patients with incomplete lymphadenectomy, 75% of regional node recurrence occurred outside of the dissected sites. Complete lymphadenectomy is shown to be a likely predictive factor of reduced risk of recurrence at the regional nodes by multivariate analysis, after adjusting for patient age, pathological T stage, and pathological nodal metastases.

Conclusions

This study shows that template-based lymphadenectomy reduced the risk of regional node recurrence in patients with urothelial carcinoma of the renal pelvis and appears to result in improved survival.


Patients with malignant mesothelioma typically present with a pleural effusion or pleural thickening and masses. A rare autopsy case of mesothelioma presenting with multiple bilateral lung nodules without clinically detectable pleural lesions is presented. A definitive diagnosis of the video-assisted thoracic surgery specimen could not be made, though a pattern of fibrosis mimicking organizing pneumonia was identified. Despite corticosteroid therapy, follow-up chest computed tomography showed enlargement of multiple nodules accompanied by the appearance of pleural thickening and effusions. The patient died of respiratory failure 11 months after initial presentation. Autopsy and retrospective analysis of the video-assisted thoracic surgery specimen using a p16 fluorescence in situ hybridization assay showed p16 homozygous deletion. The final diagnosis was sarcomatoid mesothelioma, and the lung nodules were intrapulmonary metastases from a clinically undetectable pleural sarcomatoid mesothelioma. It is important both to consider the possibility of mesothelioma with unusual clinical, radiological and pathological presentations and to remember that p16 fluorescence in situ hybridization analysis can play an important role in the diagnosis of mesothelioma.


The proband was a 32-year-old man with sparse type of familial adenomatous polyposis with fundic gland and duodenal polyps and congenital hypertrophy of the retinal pigment epithelium without osteoma, dental abnormalities and desmoid tumors. Direct DNA sequencing did not detect germline mutations in any APC exon. However, using the multiplex ligation-dependent probe amplification method, we detected germline deletions of all APC exons. Using dual-color fluorescence in situ hybridization, we identified germline deletion of locus 5q22.1–22.2 that includes APC. Analysis of colorectal tumors identified somatic APC mutations in the cluster region in all polyps, but no loss of heterozygosity was detected in any polyp.