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Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology - RSS feed of current issue

Clinical practice guidelines for pancreatic cancer based on evidence-based medicine (2006) were published by the Japan Pancreas Society (Committee for revision of clinical guidelines for pancreatic cancer) in March 2009 in Japanese, revised to Clinical Practice Guidelines for Pancreatic Cancer based on evidence-based medicine (2009) in July 2009 in Japanese and further revised to Clinical Practice Guidelines for Pancreatic Cancer (2013) in October 2013 in Japanese. These guidelines were established according to evidence-based medicine. A total of 629 papers were collected from among 4612 reports concerning pancreatic cancer listed in PubMed and Igakuchuo Zasshi between May 2007 and January 2011. This new set of guidelines was written by members of the Committee for the Revision of Clinical Practice Guidelines for Pancreatic Cancer in the Japan Pancreas Society. The guidelines provide an algorithm for the diagnosis (Fig. 1) and treatment (Fig. 2) of pancreatic cancer and address six subjects (Diagnosis, Surgery, Adjuvant therapy, Radiation therapy, Chemotherapy and stent therapy), with 35 clinical questions and 57 recommendations.


Objective

Over 70% of breast cancers are estrogen receptor alpha-positive, and endocrine therapy targeting estrogen action decreases mortality from breast cancer. Recently, a novel protein kinase that regulates estrogen receptor alpha activity, lemur tyrosine kinase-3, has been identified. In this study, we investigated whether messenger RNA expression and polymorphisms of the gene encoding the kinase, LMTK3, are associated with prognosis in breast cancer patients during long-term follow-up.

Methods

First, we investigated the relationship between messenger RNA expression of LMTK3 and patient outcome in 219 breast cancers. The effects of several variables on survival were tested by Cox proportional hazards regression analysis. Next, we performed LMTK3 genotyping in 471 breast cancers to clarify the prognostic role of these polymorphisms.

Results

Our data showed that LMTK3 expression level was not associated with prognosis in all patients. We then analyzed the impact of LMTK3 mRNA expression on the prognosis of breast cancer according to estrogen receptor alpha status. Both disease-free survival and overall survival were significantly shorter in estrogen receptor alpha-positive patients with high LMTK3 expression receiving adjuvant endocrine therapy than in those patients with low LMTK3 expression. Multivariate Cox regression analysis revealed that high LMTK3 expression was an independent poor prognostic factor in estrogen receptor alpha-positive breast cancer patients. We did not find any correlation between LMTK3 genotypes and prognosis of breast cancer patients in our series.

Conclusions

Our results show that high expression of LMTK3 is an independent prognostic factor in estrogen receptor alpha-positive breast cancer patients receiving adjuvant endocrine therapy.


Objective

The Japanese classification of peritoneal metastases from colorectal cancer is easy to use for general surgeons in routine clinical practice. However, the objectivity of this classification has not been determined. This study aimed to clarify the objectivity of the Japanese classification of peritoneal metastases from colorectal cancer.

Methods

The data of patients with Stage IV colorectal cancer between 1991 and 2007 in 16 hospitals, who were members of the Japanese Society for Cancer of the Colon and Rectum, were investigated. The size, number and extent (nine areas) of peritoneal metastases according to the Japanese classification (P1, P2 and P3) were investigated using Akaike's information criterion.

Results

Of the 564 colorectal cancer patients with synchronous peritoneal metastases, 341 had hematogenous metastases. The minimum Akaike's information criterion was obtained with the cutoff value of one area for P1 metastasis and two or more areas for P2 metastasis (P < 0.0001). When P2 metastasis was compared with P3 metastasis, the cutoff value of the number of peritoneal metastases was 10.

Conclusions

The present study proposes a revision that would give objectivity to the present Japanese classification as follows: P1 is defined as peritoneal metastases 20 mm or smaller confined to one area; P2 is defined as 10 or fewer peritoneal metastases disseminated in two or more areas, or peritoneal metastases confined to one area but the size is >20 mm and P3 is defined as >10 peritoneal metastases disseminated in two or more areas.


Objective

In patients with endometrial cancer, obesity is associated with a well-differentiated histological grade but not with prolonged survival. It is possible that this lack of survival advantage is caused by incomplete surgical staging.

Methods

In total, 716 patients with endometrial cancer were retrospectively reviewed. Obesity was defined as body mass index of ≥30 kg/m2. The relationships between clinicopathological factors and disease-specific survival were analyzed by Cox regression analysis.

Results

Older age (hazard ratio, 1.6; 95% confidence interval, 1.1–2.4), advanced stage (hazard ratio, 11.2; 95% confidence interval, 7.2–17.5), high-risk histology (hazard ratio, 2.7; 95% confidence interval, 1.8–4.0), no hysterectomy (hazard ratio, 3.1; 95% confidence interval, 1.7–5.8) and no lymphadenectomy (hazard ratio, 2.0; 95% confidence interval, 1.3–3.0) were independently associated with poor disease-specific survival. Survival was similar in obese and non-obese women (hazard ratio, 0.9; 95% confidence interval, 0.5–1.6) despite the fact that obesity was significantly associated with younger age and a well-differentiated histological grade. Although there was no difference in the distribution of disease stage between the two groups, obesity was associated with lower rates of hysterectomy (3.6 vs. 6.1%, P = 0.23) and lymphadenectomy (25.0 vs. 36.4%, P = 0.017). Obese patients who underwent hysterectomy had a significantly better disease-specific survival than those who did not (P = 0.002). The 5-year disease-specific survival rate in obese patients who underwent lymphadenectomy was 6.2% better than that in those who did not [86.0 vs. 79.8%, P = 0.36 (not statistically significant)].

Conclusion

Poor-quality surgical staging in obese women may result in worse than expected survival outcomes.


Objective

Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.

Methods

Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.

Results

Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26–2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25–1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.

Conclusions

The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.


Objective

The purpose of this study is to identify factors that affect survival of patients with differentiated thyroid carcinoma with bone metastases and to optimize surgical treatment modality for bone metastatic lesion by comparing duration of patient survival and local control.

Methods

We examined 52 bone metastatic lesions from 40 patients with differentiated thyroid carcinoma who were treated surgically between 1994 and 2008 at Keio University Hospital. Median follow-up time was 46 months (range: 4–233 months). Patients' disease-specific survival, local control duration and factors that potentially affected disease-specific survival after bone metastasis surgery were statistically analyzed.

Results

The 2-, 5- and 10-year disease-specific survival rates were 77.2, 64.3 and 45.7%, respectively. Factors that were significantly associated with poor survival rates in multivariate analyses included age at bone metastasis surgery ≥65 years (P = 0.0068), time from diagnosis of primary cancer to bone metastasis surgery ≥5 years (P = 0.0018) and presence of visceral metastases (P = 0.0092). The 2-, 5- and 10-year local control rates in our series were 91.4, 72.7 and 63.6%, respectively. The 5-year local control rates for radical and palliative surgery were 84.4 and 55.3%, respectively, and differed significantly (P = 0.019).

Conclusions

Because disease-specific survival of patients with differentiated thyroid carcinoma is fairly good, inadequate treatment of bone metastatic lesions can result in severe disabilities. Therefore, radical surgery for bone metastatic lesions should be considered, especially for those with favorable prognostic factors.


Objective

Solitary fibrous tumor is a rare tumor occurring in almost every anatomic location of human body; however, reports of malignant solitary fibrous tumor in the nasal and paranasal area are especially rare. In this report, we describe a case of non-recurrent malignant solitary fibrous tumor of the nasal and paranasal area.

Methods

The patient was initially treated with nasal and paranasal tumor cytoreductive surgery, followed by post-operative three-dimensional conformal intensity modulated radiation therapy (dynamic MLC Varian 600CD Linac, inversely optimized by the Eclipse system) and stereotactic body radiation therapy to provide a radical cure for residual tumor.

Results

The tumor of the nasal and paranasal area was effectively treated and the integrity of the right eye kept. There were no signs of recurrence after four and a half years of further follow-up.

Conclusions

This is the first attempt to successfully combine cytoreductive surgery with intensity modulated radiation therapy and stereotactic body radiation therapy together to treat solitary fibrous tumor of the nasal and paranasal area, which may provide a potential strategy for the treatment of similar cases.


Objective

We sought to investigate general health status and late effects among adolescent and young adult survivors of childhood cancer.

Methods

We conducted a cross-sectional survey, using self-rated questionnaires on current and past health problems. Questionnaires were provided to childhood cancer survivors, a comparison group of siblings and a general population control group that was recruited online. 2 tests were used to compare responses to the 72 survey items.

Results

The final sample included 185 childhood cancer survivors (72% response rate), 72 siblings and 1000 general population controls. In the childhood cancer survivors group, the median age of diagnosis was 8 years and the median age at survey was 23 years. According to the physicians' reports, 56% of the childhood cancer survivors experienced at least one late effect. In descending order of prevalence, the current symptoms in the childhood cancer survivors group were (i) impaired visual acuity (45%), (ii) dizziness (36%) and (iii) any allergy (34%). The three most common symptoms had similar prevalence rates in each of the groups. As compared with the control group, the following physical symptoms were significantly more common in the childhood cancer survivors group: mental retardation (odds ratio: 48.6, P < 0.01); cataract (odds ratio: 29.7); suspected infertility (odds ratio: 25.1); delayed puberty (odds ratio 24.9); growth hormone deficiency (odds ratio: 23.0); and other audiovisual, urinary, endocrine, infertility, cardiovascular, respiratory, gastrointestinal, spinal, extremity and neuromuscular problems.

Conclusions

Many adolescent/young adult childhood cancer survivors could be suffering from ongoing late effects that stem from cancer and its treatment. Overall health monitoring for childhood cancer survivors can provide indispensable benefits.


Objective

To assess the patterns of recurrence in cervical cancer patients treated with pelvic nodal clinical target volume at L4–L5 junction instead of aortic bifurcation.

Methods

Records of patients with locally advanced cervical cancer treated with chemo-radiation were reviewed. Patients treated with standard pelvic fields (superior border of the field at L4/L5 junction), without any radiological evidence of regional lymphadenopathy (<10 mm) were included in the study. The level of aortic bifurcation was retrospectively documented on computed tomography. Patterns of recurrences were correlated to the aortic bifurcation and the superior border of the radiation fields (L4/L5).

Results

Aortic bifurcation was above the radiation fields (above L4/5) in 82 of 116 (70.7%) patients. Of the nine patients that recurred above the radiation field, 5 (55%) were above L4/5 failures, i.e. between aortic bifurcation and L4/5, and 4 (45%) had para-aortic failures. On retrospective analysis, 16 patients were found to have subcentimeter lymph nodes and higher nodal failures (7/16) were observed in patients with subcentimeter regional lymph nodes at diagnosis.

Conclusions

Superior border of nodal clinical target volume should ideally include the aortic bifurcation instead of L4–L5 inter space in patients with locally advanced cervical cancer. Radiotherapy fields need to be defined cautiously in patients with subcentimeter pelvic lymph nodes.


Objective

We investigated the correlation between circulating tumor cells and the incidence of brain metastases as a first site of recurrence among patients with small-cell lung cancer after systemic chemoradiotherapy and prophylactic cranial irradiation. In addition, we assessed the contribution of circulating tumor cells for planning the appropriate total dose of prophylactic cranial irradiation for small-cell lung cancer.

Methods

Patients (n = 112) with diagnosed Stage III small-cell lung cancer were treated with four cycles of platinum-based regimen and concurrent chest irradiation, and then prophylactic cranial irradiation. Blood samples for circulating tumor cell analysis were obtained before the initiation of chemotherapy and after the first and fourth cycle of chemotherapy.

Results

Circulating tumor cells after the first cycle of chemotherapy correlated with tumor response after completion of chemotherapy (P = 0.012). Patients with brain as the first site suffered a higher rate of further metastases to other organs, and local recurrence, compared with those whose first site was the other organs (P < 0.001), and their survival rates were worse. Circulating tumor cells at baseline were the sole independent prognostic factor for specific progression-free survival. Receiver operating characteristic curves based on median specific progression-free survival revealed a circulating tumor cell cutoff at baseline of 218, and circulating tumor cells ≤218 at baseline correlated with significantly higher progression-free survival (P = 0.007), specific progression-free survival (P = 0.001) and overall survival (P = 0.001).

Conclusions

Circulating tumor cells prior to the initiation of chemotherapy are a valuable predictor of specific progression-free survival in Stage III small-cell lung cancer. For patients with circulating tumor cells >218, prophylactic cranial irradiation at a total dose of 30 Gy in 15 fractions is insufficient.


Objective

Endobronchial ultrasound elastography is a new technique for describing the stiffness of tissue during endobronchial ultrasound-guided transbronchial needle aspiration. The aims of this study were to evaluate the utility of endobronchial ultrasound elastography for mediastinal and hilar lymph nodes, and to compare the elastographic patterns of lymph nodes with results from endobronchial ultrasound-guided transbronchial needle aspiration.

Methods

Seventy-five lymph nodes were evaluated. A convex probe endobronchial ultrasound was used with a new endoscopic ultrasound processor to assess elastographic patterns that were classified based on color distribution as follows: Type 1, predominantly non-blue (green, yellow and red); Type 2, part blue, part non-blue (green, yellow and red); Type 3, predominantly blue. The elastographic patterns were compared with the final pathologic results from endobronchial ultrasound-guided transbronchial needle aspiration.

Results

On pathological evaluation of the lymph nodes, 33 were benign and 42 were malignant. The lymph nodes that were classified as Type 1 on endobronchial ultrasound elastography were benign in 24/24 (100%); for Type 2 lymph nodes, 6/14 (46.9%) were benign and 8/14 (57.1%) were malignant; Type 3 lymph nodes were benign in 2/37 (5.4%) and malignant in 35/37 (94.6%). In classifying Type 1 as ‘benign’ and Type 3 as ‘malignant,’ the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy rates were 100, 92.3, 94.6, 100 and 96.7%, respectively.

Conclusions

Endobronchial ultrasound elastography of mediastinal and hilar lymph nodes is a noninvasive technique that can be performed reliably and may be helpful in the prediction of nodal metastasis during endobronchial ultrasound-guided transbronchial needle aspiration.


Objective

The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.

Methods

A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.

Results

Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.

Conclusions

We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.


Objective

The objective of the present study was to investigate the trends over time in the initial treatment of prostate cancer in Japan.

Methods

A total of 8291 patients with newly diagnosed prostate cancer whose treatment started in 2010 were registered in a multi-institutional observational study undertaken nationwide across Japan by the Japan Prostate Cancer Study Group. Each patient's background characteristics and initial treatment were recorded.

Results

The median age at diagnosis was 71 years. The proportion of T1c disease was 40.5% and that of M1 disease was 10.4%. The prostate-specific antigen level was <10 ng/ml in 52.0% of the patients. High-, intermediate- and low-risk patients as determined by D'Amico's classification system made up 19.3, 29.8 and 25.9% of the cases, respectively. The initial treatment was androgen depletion therapy in 40.2%, radical prostatectomy in 32.0% (17.3% of these involved laparoscopic prostatectomy), radiation in 21.0% (46.4% of these involved brachytherapy). In cases of organ-confined disease, radical prostatectomy was selected in 39.5%, androgen depletion therapy in 28.0% and radiation in 23.9%. In D'Amico's low-risk group, the proportion treated with radiation was nearly equal to that treated with radical prostatectomy (30.2 and 32.7%, respectively); 73.2% of the radiation treatments involved brachytherapy.

Conclusion

Compared with previous Japanese studies, radiation use was increased by ~10%. This increased proportion of radiation use was a typical trend in initial therapy for newly diagnosed prostate cancer cases in Japan. Although androgen depletion therapy use was decreased, it was selected in a high proportion of the patients irrespective of the disease stage.


Mesenchymal tumors are thought to constitute only 1% of primary gastrointestinal malignancies. Both gastrointestinal stromal tumor and desmoid tumor are rare. The case of a 56-year-old male with a desmoid tumor 1 year after surgical removal of a gastrointestinal stromal tumor near the ligament of Treitz is described. Although he received adjuvant therapy of imatinib mesylate for 1 year after the surgery, a small nodule was found 1 year and 3 months after the surgery. The nodule was considered to be a recurrent tumor of gastrointestinal stromal tumor, and a wedge resection of the duodenum including the tumor was done. Histopathological examination by immunohistochemical staining revealed that it was a desmoid tumor. It would be useful to be aware of the possibility of desmoid tumor after removal of gastrointestinal stromal tumor. To accumulate further information on these rare diseases, a central database that includes rare diseases will be necessary.


Objective

The potential associations of diabetes mellitus with malignant neoplasms including liver cancer have become a great concern from both clinical and preventive perspectives. Although sufficient evidence for a positive association between diabetes and liver cancer already exists, it would be informative to summarize up-to-date epidemiologic data in Japan.

Methods

We systematically reviewed epidemiologic studies on diabetes and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence (‘convincing’, ‘probable’, ‘possible’ or ‘insufficient’), together with biological plausibility.

Results

We identified 19 cohort studies, one pooled-analysis of seven cohort studies, and seven case–control studies. Of 24 relative risk estimates of liver cancer for diabetes reported in those cohort studies, 17 showed a weak to strong positive association, six revealed no association and one demonstrated a weak inverse association (summary relative risk 2.10, 95% confidence interval 1.60–2.76). Ten relative risk estimates from the case–control studies showed a weak to strong positive association (n = 9) or no association (n = 1; summary relative risk 2.32, confidence interval 1.73–3.12). Overall, the summary relative risk became 2.18 (confidence interval 1.78–2.69). Heterogeneity in relative risks was significant for the difference in categories of study population (P = 0.01), but not in study type (P = 0.39) or sex (P = 0.33).

Conclusions

Diabetes mellitus ‘probably’ increases the risk of liver cancer among the Japanese population.


We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16–25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.


Juvenile polyposis syndrome is an autosomal dominant inherited disorder characterized by multiple juvenile polyps arising in the gastrointestinal tract and an increased risk of gastrointestinal cancers, specifically colon cancer. BMPR1A and SMAD4 germline mutations have been found in patients with juvenile polyposis syndrome. We identified a BMPR1A mutation, which involves a duplication of coding exon 3 (c.230+452_333+441dup1995), on multiple ligation dependent probe amplification in a patient with juvenile polyposis syndrome. The mutation causes a frameshift, producing a truncated protein (p.D112NfsX2). Therefore, the mutation is believed to be pathogenic. We also identified a duplication breakpoint in which Alu sequences are located. These results suggest that the duplication event resulted from recombination between Alu sequences. To our knowledge, partial duplication in the BMPR1A gene has not been reported previously. This is the first case report to document coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome.


In seeking to understand how life-threatening illness affects children psychologically, projective testing may be beneficial, particularly when attempting to identify psychological problems in younger adolescents. The advantages of projective testing are that it does not depend on patients' verbal ability and is not invasive. Three cancer inpatients from Kyoto Prefectural University of Medicine, aged between 10 and 16 years old, participated in the study. Projective testing was used to measure the depth of participants' distress and included a tree-drawing test, a person-drawing test and a free drawing test. Results from the tree- and person-drawing tests indicated energy loss, anxiety and a sense of emptiness. However, results from the free drawing test suggested that the children had hope and a desire to recover from their illness. The combination of drawing tests in this study may increase the understanding of the internal psychological difficulties faced by children hospitalized with cancer.