Showing papers in "Japanese Journal of Clinical Oncology in 2015"

Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project

Abstract: The Japan Cancer Surveillance Research Group aimed to estimate the cancer incidence in Japan in 2009 based on data collected from 32 of 37 population-based cancer registries, as part of the Monitoring of Cancer Incidence in Japan (MCIJ) project. The incidence of only primary invasive cancer in Japan for 2009 was estimated to be 775 601. Stomach cancer and breast cancer were the leading types of cancer in males and females, respectively.

An updated report on the trends in cancer incidence and mortality in Japan, 1958–2013

Abstract: The analysis of cancer trends in Japan requires periodic updating. Herein, we present a comprehensive report on the trends in cancer incidence and mortality in Japan using recent population-based data. National cancer mortality data between 1958 and 2013 were obtained from published vital statistics. Cancer incidence data between 1985 and 2010 were obtained from high-quality population-based cancer registries of three prefectures (Yamagata, Fukui and Nagasaki). Joinpoint regression analysis was performed to examine the trends in age-standardized rates of cancer incidence and mortality. All-cancer mortality decreased from the mid-1990s, with an annual percent change of -1.3% (95% confidence interval [CI]: -1.4, -1.3). During the most recent 10 years, over 60% of the decrease in cancer mortality was accounted for by a decrease in stomach and liver cancers (63% for males and 66% for females). The long-term increase in female breast cancer mortality, beginning in the 1960s, plateaued in 2008. All-cancer incidence continuously increased, with annual percent changes of 0.6% (95% CI: 0.5, 0.8) between 1985 and 2005, and 1.8% (95% CI: 0.6, 2.9) between 2005 and 2010. During the most recent 10 years, almost half of the increase in cancer incidence was accounted for by an increase in prostate cancer (60%) in males and breast cancer (46%) in females. The cancer registry quality indices also began to increase from ∼2005. Decreases in stomach and liver cancers observed for incidence and mortality reflect the reduced attribution of infection-related factors (i.e. Helicobacter pylori and hepatitis virus). However, it should be noted that cervical cancer incidence and mortality rates began to increase from ∼1990.

Quality assessment and improvement of nationwide cancer registration system in Taiwan: a review

Abstract: Cancer registration provides core information for cancer surveillance and control. The populationbased Taiwan Cancer Registry was implemented in 1979. After the Cancer Control Act was promulgated in 2003, the completeness (97%) and data quality of cancer registry database has achieved at an excellent level. Hospitals with 50 or more beds, which provide outpatient and hospitalized cancer care, are recruited to report 20 items of information on all newly diagnosed cancers to the central registry office (called short-form database). The Taiwan Cancer Registry is organized and funded by the Ministry of Health and Welfare. The National Taiwan University has been contracted to operate the registry and organized an advisory board to standardize definitions of terminology, coding and procedures of the registry’s reporting system since 1996. To monitor the cancer care patterns and evaluate the cancer treatment outcomes, central cancer registry has been reformed since 2002 to include detail items of the stage at diagnosis and the first course of treatment (called long-form database). There are 80 hospitals, which count for >90% of total cancer cases, involved in the long-form registration. The Taiwan Cancer Registry has run smoothly for >30 years, which provides essential foundation for academic research and cancer control policy in Taiwan.

Long non-coding RNA UCA1 promotes glutamine metabolism by targeting miR-16 in human bladder cancer

Abstract: Objective Long non-coding ribonucleic acid urothelial carcinoma-associated 1 has been found to be a participant in cancer development and glucose metabolism in bladder cancer. However, the role of urothelial carcinoma-associated 1 in metabolic reprogramming in cancer remains to be clarified. In this study, we aim to elucidate the molecular mechanism underlying the regulation of glutamine metabolism by urothelial carcinoma-associated 1 in bladder cancer. Methods The RNA levels of urothelial carcinoma-associated 1, GLS2 and miR-16 in bladder tissues and cell lines were examined by real-time reverse transcriptase-polymerase chain reaction. The protein levels of GLS2 were detected by western blot analysis. Reactive oxygen species generation was examined by the fluorescein isothiocyanate mean value and fluorescence microscope. Glutamine consumption was analyzed using the glutamine assay kit. Additionally, we performed luciferase reporter assays to validate urothelial carcinoma-associated 1 sequence whether contains miR-16 binding site and the interaction between the 3'UTR sequence of GLS2 and mature miR-16. Results Real-time reverse transcriptase-polymerase chain reaction demonstrated that the RNA level of urothelial carcinoma-associated 1 and GLS2 was positively correlated in bladder cancer tissues and cell lines. The expression of GLS2 mRNA and protein increased in cells which overexpression of urothelial carcinoma-associated 1 and decreased in cells which knocked-down of urothelial carcinoma-associated 1 cell lines. urothelial carcinoma-associated 1 reduced ROS production, and promoted mitochondrial glutaminolysis in human bladder cancer cells. Furthermore, luciferase reporter assays indicated that there was a miR-16 binding site in urothelial carcinoma-associated 1, and it showed appreciable levels of sponge effects on miR-16 as readouts in a dose-dependent manner. Moreover, the 'seed region' of miR-16 directly bound to the 3'UTR of GLS2 mRNA and regulated GLS2 expression level. Conclusions Together, our results revealed that urothelial carcinoma-associated 1 regulated the expression of GLS2 through interfering with miR-16, and repressed ROS formation in bladder cancer cells.

Prognostic value of neutrophil-lymphocyte ratio and level of C-reactive protein in a large cohort of pancreatic cancer patients: a retrospective study in a single institute in Japan.

Abstract: Objective Recent studies suggest that systemic inflammatory response is closely associated with cancer patient prognosis. Although several inflammatory prognostic markers have been proposed, the data to support their validity are lacking in large Japanese cohorts. Methods This is a retrospective study to examine the prognostic value of inflammatory markers, such as C-reactive protein, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and modified Glasgow prognostic scale, in pancreatic cancer. Selection criteria were admittance to hospital between January 2008 and December 2012, histologically confirmed adenocarcinoma, diagnosis of invasive ductal pancreatic cancer compatible by computed tomography imaging, and followed-up until death or for 180 days or longer. The primary end point was overall survival, which was measured from the day of histological diagnosis. Results There were 440 patients who met the selection criteria. Of the 440 cases, 200 (45.5%) received curative resection (166 Stage I/II and 34 Stage III patients), 237 (53.9%) received chemotherapy (4 Stage I/II, 92 Stage III and 141 Stage IV patients), and the remaining 3 received palliative care. Univariate and multivariate regression analyses revealed that advanced computed tomography stage, high level of C-reactive protein (0.45 mg/dl or greater), neutrophil-lymphocyte ratio (2.0 or greater) and CA19-9 level (1000 U/ml or greater) were significantly associated with worse prognosis. Conclusions We verified the results of previous studies, and showed that neutrophil-lymphocyte ratio and C-reactive protein also had prognostic value in a large Japanese PC cohort.

The association between overweight, obesity and ovarian cancer: a meta-analysis

Abstract: Objective Epidemiological studies have reported an inconsistent association between obesity and ovarian cancer. To update the current knowledge of and further qualify the association between overweight, obesity and ovarian cancer risk, we conducted a meta-analysis of published observational studies. Methods Using the PubMed, MEDLINE and EMBASE databases, we performed a literature search of all of the case-control and cohort studies published as original articles in English before March 2015. We included 26 observational studies, of which 13 were case-control studies (7782 cases and 21 854 controls) and 13 were cohort studies (5181 cases). Fixed- and random-effects models were used to compute summary estimates and the corresponding 95% confidence intervals. Subgroup analyses were also performed. Results The pooled relative risk for overweight and obesity compared with normal weight (body mass index = 18.5-24.9 kg/m(2)) was 1.07 (95% confidence interval: 1.02-1.12) and 1.28 (95% confidence interval: 1.16-1.41), respectively. In subgroup analyses, we found that overweight/obesity increased the risk of ovarian cancer in most groups, except for the postmenopausal group (overweight: pooled relative risk = 0.97, 95% confidence interval: 0.76-1.24; obesity: pooled relative risk = 0.93, 95% confidence interval: 0.61-1.42). There was no evidence of publication bias. Conclusions Increased body weight was associated with an increased risk of ovarian cancer; in particular, severe obesity demonstrated a stronger risk effect. No statistically significant association was observed in the postmenopausal period, but was in the premenopausal period.

Transformation to small-cell lung cancer as a mechanism of acquired resistance to crizotinib and alectinib

Abstract: A 56-year-old woman, a never-smoker, had postoperative recurrence of anaplastic lymphoma kinase rearranged lung cancer. She achieved a partial response to treatment with an anaplastic lymphoma kinase tyrosine kinase inhibitor, crizotinib. After the tumor regrowth, crizotinib was switched to alectinib; once again a partial response was observed. At the second recurrence, transbronchial needle aspiration of the right paratracheal node was performed, which revealed cytological findings of small-cell carcinoma. While treatment with cisplatin-irinotecan chemotherapy made reduction of some tumor shadows, including the biopsied mediastinal lymph nodes, new, small, nodular shadows, highly suggestive of pulmonary metastases, were detected in both lung fields. This case may show proof of the transformation to small-cell lung cancer as a mechanism of resistance to anaplastic lymphoma kinase tyrosine kinase inhibitors in anaplastic lymphoma kinase rearranged tumor. However, this transformation may also be only one part of the resistance mechanism of the heterogeneous tumor.

Implementation of cervical cancer screening and prevention in China—challenges and reality

Abstract: This article summarizes great efforts that Chinese scholars had made in fighting against cervical cancer from aspects of the epidemiology, etiology, population-based screening studies, novel screening technology development, guideline, strategy and policy making and population delivery. After decades of continuous efforts, Chinese scientists successfully translated their scientific discovery to appropriate screening product development and eventually, delivered it to the whole population. We hope our experience could serve as a 'case-story' for cancer prevention in other low- and middle-income countries. Moreover, challenges confronted in the prevention and control of cervical cancer in China are reviewed as well to appeal for future multi-collaborations and potential solutions to acquire the final success of the campaign.

Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients

Abstract: Objective: This prospective, post-marketing study collected sunitinib safety and efficacy data in Japanese patients with unresectable/metastatic renal cell carcinoma. Retrospective analysis investigated adverse events as potential sunitinib efficacy biomarkers. Methods: Patients administered sunitinib, after its release, were registered until reaching a pre-specified number of cases. Primary starting dose was 50 mg/day orally on a 4-weeks-on and 2-weeks-off schedule. Physicians completed investigation forms at 6-week intervals for 24 weeks. Associations between baseline characteristics and adverse events were analyzed by Cox proportional hazards model and compared by χ 2 test. The log-rank test compared survival in subpopulations based on selected factors. Results: Of note, 1689 patients receiving sunitinib were registered between June 2008 and November 2009. Most of them were males (75%), aged <65 years (56%), and had Eastern Cooperative Oncology Group performance status 0/1 (90%), metastatic disease (88%) and previous systemic therapy (66%). Grade ≥3 adverse events occurred in 70%, with reduced platelet count the most common (34%). Characteristics significantly associated with Grade ≥3 adverse events were female sex, age ≥55 years, Eastern Cooperative Oncology Group performance status ≥2, history of several medical conditions and prior treatment. Objective response rate was 22%. Median progression-free survival was 22.7 weeks. Median overall survival was not reached; however, 24-weekoverall survival ratewas 84%. Improved overall survival was associated with higher relative dose intensity during the first 6 weeks and specific adverse events: hypertension, hand–foot syndrome, hypothyroidism, leukopenia and thrombocytopenia. Conclusions: Sunitinib demonstrated acceptable safety and useful efficacy in Japanese patients with unresectable/metastatic renal cell carcinoma. Potential biomarkers associated with greater efficacy were relative dose intensity and specific adverse events.

A randomized Phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study)

Abstract: Pre-operative chemotherapy with S-1 plus cisplatin is considered to be acceptable as one of the standard treatment options for gastric cancer patients with extensive lymph node metastases in Japan. Addition of trastuzumab to chemotherapy is shown to be effective for HER2-positive advanced gastric cancer patients, and we have commenced a randomized Phase II trial in March 2015 to evaluate S-1 plus cisplatin plus trastuzumab compared with S-1 plus cisplatin alone in the neoadjuvant setting for HER2-positive gastric cancer patients with ELM, which are followed by adjuvant chemotherapy with S-1 for 1 year. A total of 130 patients will be accrued from 41 Japanese institutions over 3 years. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate of pre-operative chemotherapy, proportion of patients with R0 resection, proportion of patients who complete the pre-operative chemotherapy and surgery, proportion of patients who complete the protocol treatment including post-operative chemotherapy, pathological response rate and adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN 000016920.

Systematic lymphadenectomy in the treatment of epithelial ovarian cancer: a meta-analysis of multiple epidemiology studies

Abstract: Objective: To evaluate the role of systematic lymphadenectomy in epithelial ovarian cancer by comparing 5-year overall survival rates between systematic and unsystematic lymphadenectomies. Methods: A literature search of the Pubmed, Embase and Cochrane Library databases was performed up to 2014. Two authors independently determined the eligibility of the articles and extracted the available data. The role of systematic lymphadenectomy in epithelial ovarian cancer was analyzed by combining all qualifiedindividualstudiesusinga fixed-effect model. Then, subgroup analysis was performed by dividing articles according to type, cancer stage and residual tumor. Finally, heterogeneity and publication bias in all enrolled studies were assessed using HigginsI 2 statistics and funnel plots, respectively. Results: Fourteen relevant studies including 3488 subjects were included in the analysis. The value of pooled relative ratios of all qualified studies revealed that the 5-year overall survival rate in the lymphadenectomy group was higher than that in the unsystematic lymphadenectomy group (relative ratio = 1.08; P= 0.001), which was duplicated in the subgroup analysis of observational studies (relative ratio = 1.07; P= 0.002) and advanced stage (relative ratio = 1.21; P= 0.012) epithelial ovarian cancer. No significant differences were observed in randomized controlled trials (relative ratio = 1.01; P= 0.858), early stage epithelial ovarian cancer (relative ratio = 1.06; P= 0.064) or patients with residual tumor ≤2 cm (relative ratio = 1.05; P = 0.125). The heterogeneity and publication bias in the enrolled studies were within acceptable thresholds. Conclusions: Lymphadenectomy can improve the 5-year overall survival rate in advanced stage epithelial ovarian cancer but not in early stage epithelial ovarian cancer or in patients with residual tumor ≤2 cm.

Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma.

Abstract: OBJECTIVE To investigate the prognostic significance of visceral obesity to predict recurrence after curative surgery for Japanese patients with localized renal cell carcinoma. METHODS The data of 285 patients who underwent curative surgery for localized renal cell carcinoma were retrospectively reviewed. Median follow-up was 36.7 months. The association between visceral obesity and recurrence-free survival rate was evaluated using the Kaplan-Meier method and Cox regression models. Visceral fat area at the level of the umbilicus measured using pre-operative computed tomography was used as an index of visceral obesity. RESULTS Twenty-nine patients (10.2%) experienced recurrence. Five-year recurrence-free survival rates were 91.3% in high visceral fat area group (≥ 120 cm(2)) and 76.9% in low visceral fat area group (<120 cm(2)) (P = 0.037); however, visceral fat area was not an independent predictor of recurrence-free survival in multivariate analysis. In the patients with clear cell renal cell carcinoma, 28 patients (11.6%) experienced recurrence. Five-year recurrence-free survival rates were 88.7% in high visceral fat area group and 71.0% in low visceral fat area group (P = 0.043), and visceral fat area was an independent predictor of recurrence-free survival (hazard ratio: 1.974, P = 0.042) as well as C-reactive protein, Fuhrman nuclear grade, tumor size and microvascular invasion. In patients with organ confined clear cell renal cell carcinoma in particular, visceral fat area was also a useful and independent predictor of recurrence-free survival (hazard ratio: 2.807, P = 0.038). Body mass index was not useful in either cohort. CONCLUSIONS High visceral fat area was a positive predictive biomarker for better recurrence-free survival after curative surgeries for localized clear cell renal cell carcinomas; however, body mass index was not a predictor.

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1

Abstract: Objective Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. Methods The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. Results We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. Conclusions miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.

Anatomic-histologic study of the floor of the mouth: the lingual lymph nodes.

Abstract: Objective The lingual lymph nodes are inconstant nodes located within the fascial/intermuscular spaces of the floor of the mouth. Oral tongue squamous cell carcinoma has been reported to recur and metastasize in lingual lymph nodes with poor prognosis. Lingual lymph nodes are not currently included in basic tongue squamous cell carcinoma surgery. Methods Twenty-one cadavers (7 males, 14 females) were studied, aged from 57 to 94 years (mean age 76.3 years). The gross specimen of the floor of the mouth was divided into blocks: A (median nodes), B, B' (parahyoid), C, C' (paraglandular). Serial histological microslides were cut and stained with hematoxylin-eosin. Frequency of lingual lymph nodes in each block and their microscopic features were assessed. Results The lingual lymph nodes in overall number of 7 were detected in 5 of the 21 cadavers (23.8%). The total incidence of lingual lymph node was 33.3% (7 nodes/21 cadavers). Block A failed to demonstrate any lymph nodes (0%); Blocks B, B'-2 nodes (9.5%) and 2 nodes (9.5%), respectively; Blocks C, C'-1 node (4.8%) and 2 nodes (9.5%), respectively. The mean lingual lymph node length was 4.1 mm (from 1.4 to 8.7 mm), the mean thickness was 2.8 mm (from 0.8 to 7.5 mm). Five cadavers (23.8%) revealed mucosa-associated lymphoid tissue. Atrophic changes appeared in 4 (57.1%) lingual lymph nodes. Conclusion The presence of lymph node-bearing tissue in the floor of the mouth is demonstrated. In account of resection radicalism and better local control the fat tissue of the floor of the mouth should be removed in conjunction to glossectomy. Further anatomic and clinical research is required to establish the role of lingual lymph node in oral squamous cell carcinoma recurrence and metastasis.

Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304).

Abstract: Objective The efficacy of perioperative chemotherapy for soft tissue sarcomas is controversial and only a few prospective studies of pre-operative chemotherapy for soft tissue sarcomas in the extremities have been reported. We therefore carried out Phase II study of perioperative chemotherapy for patients with soft tissue sarcomas in the extremities. Methods Patients with Stage III non-round cell soft tissue sarcomas in the extremities were eligible. The patients were treated with pre-operative chemotherapy consisting doxorubicin 60 mg/m(2) and ifosfamide 10 g/m(2) for three courses. After the tumor resection, two additional courses of the same regimen were carried out. Results A total of 72 patients were enrolled and 70 patients were eligible. The median age of the patients was 49 years. The major pathological subtypes were synovial sarcoma in 20 and undifferentiated pleomorphic sarcoma in 17 patients. The protocol treatments were completed in 74% of the eligible cases. The 2 and 5-year progression-free survival rates were 75.7% (95% CI, 63.9-84.1%) and 63.8% (95% CI, 51.3-73.9%), respectively. The 5-year overall survival was 82.6% (95% CI, 71.3-89.7%). There was no treatment-related death. Grade 3 or 4 hematological toxicities (leukopenia and neutropenia) were observed in most of the patients. Conclusions Although the toxicities of the regimen were significant, pre-operative chemotherapy followed by post-operative chemotherapy using doxorubicin and high-dose ifosfamide was feasible. The outcome of the trial for the patients with high-grade soft tissue sarcomas in the extremities was favorable, and this regimen is promising for further investigation. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as C000000096.

Morphological distribution of lung cancer from Cancer Incidence in Five Continents Vol. X.

Abstract: To compare the morphological distribution of cancer incidence worldwide, we abstracted the incidence in 2003–07 fromCancer Incidence in Five Continents Vol. X (CI5-X). The International Agency for Research on Cancer provides the CI5 detailed databases on the incidence of cancer recorded by cancer registries (regional and national) worldwide. We used the number of incidences in Japan, the Republic of Korea, the USA, Brazil, UK, Italy and Australia from the CI5 database which contains the incidence for selected cancer registries published in CI5-X for 2003–07. The Republic of Korea and the USA (NPCR: National Program of Cancer Registries) reported the cancer incidence covered by all the country; however, the remaining countries reported the cancer incidence by registry. We aggregated eight registries in Japan, two registries in Brazil, four registries in the UK, 22 registries in Italy and five registries in Australia. We compared the morphological distribution between countries for lung cancer coded as C34 (ICD10). The incidence of lung cancer was ranked in the top three for males and in the top six for females in all the countries studied. The age-standardized rates of lung cancer (including trachea cancer coded as C33) by world standard population (/100 000) were 42.7 in Japan, 49.8 in the Republic of Korea, 53.5 in the USA, 28.2 in Brazil, 44.9 in UK, 49.0 in Italy and 74.2 in Australia for males; 14.4 in Japan, 13.4 in the Republic of Korea, 36.4 in the USA, 12.9 in Brazil, 27.7 in UK, 11.6 in Italy and 19.7 in Australia for females. These rates were average values for several registries in some selected countries as described earlier. Figure 1 shows the distribution of morphology for males; Figure 2 shows these data for females. Squamous cell carcinoma (SCC), adenocarcinoma, small-cell carcinoma and large cell carcinoma made up ∼60% of all lung cancers, and 12–35% were unspecified morphology for both sexes. Sarcoma and other morphology were rarely classified. For males, adenocarcinoma was the first or the second most common morphology in all the countries. In Korea, >30% of the patients diagnosed with lung cancer had SCC. The proportion of SCC was ∼20% in other countries. The proportion of large cell carcinoma was important in Brazil, Italy and Australia and accounts for 17.9, 12.4 and 13.2%. In the USA, the UK and Australia, other specified carcinoma was common, at 20.8, 12.9 and 12.7%, respectively. For females, a wide variety of distribution of morphology was observed. In all the countries, adenocarcinoma was the predominant morphology, especially in Japan and the Republic of Korea, where it represents approximately half of all lung cancers. Adenocarcinoma was the most frequent morphology, representing ∼30% of all lung cancers in the USA, Brazil, Italy and Australia as well. In UK, adenocarcinoma was still the most frequent; however, SCC, small-cell carcinoma, and other specified carcinoma were also apparent. In the USA, UK and Australia, SCC and other specified carcinoma were often observed, at 10–14% and 12–20%, respectively.

Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study (JFMC39-0902)

Abstract: Objective This exploratory trial was performed to determine whether Daikenchuto accelerates recovery of gastrointestinal function in patients undergoing open colectomy for colon cancer.

Development of Cell-Cycle Checkpoint Therapy for Solid Tumors

Abstract: Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors.

Prognostic value of Aurora kinase A (AURKA) expression among solid tumor patients: a systematic review and meta-analysis

Abstract: Objective: The prognostic significance of Aurora kinase A expression in cancer patients is currently under debate. Here, we conducted the first comprehensive meta-analysis of the prognostic relevance of Aurora kinase A associated with survival in solid tumors. Methods: Pubmed was searched for studies evaluating the Aurora kinase A expression and survival in solid tumors through 10 October 2014. The main outcome analyzed was overall survival and secondary outcomes were progression-free survival, disease-free survival and cancer-specific survival. Pooled hazard ratio and 95% confidence intervals were calculated to assess the association. Subgroup and sensitivity analyses were also conducted. Results: Thirty-nine eligible studies enrolling 5523 patients were identified. The high Aurora kinase A expression level was significantly associated with shorter overall survival (hazard ratio = 2.31; 95% confidence interval, 1.81–2.95). Further subgroup analyses showed that our results were stable irrespective of the disease sites, stages and methods of Aurora kinase A expression. The high Aurora kinase A expression level was also associated with progression-free survival (hazard ratio = 2.68; 95% confidence interval, 1.96–3.69), disease-free survival (hazard ratio = 1.91; 95% confidence interval, 1.45–2.51) and cancer-specific survival (hazard ratio = 2.13; 95% confidence interval, 1.38–3.29). Conclusions: Our present meta-analysis indicates that the Aurora kinase A is an effective prognosticator in solid tumors patients. Further studies are required to explore the clinical utility of Aurora kinase A in solid tumor.

MiR-501-5p regulates CYLD expression and promotes cell proliferation in human hepatocellular carcinoma

Abstract: Objective Previous studies have shown that the micro-ribonucleic acid miR-501-5p is upregulated in hepatocellular carcinoma cells and tissues with high hepatitis B virus replication, and that miR-501 overexpression significantly promotes hepatitis B virus replication. We further analysed a published microarray-based high-throughput dataset (NCBI/GEO/GSE36915) and found that miR-501-5p was upregulated in hepatocellular carcinoma tumour tissues. We therefore investigated the possible function of miR-501-5p during the development of hepatocellular carcinoma. Methods Expression of miR-501-5p in human hepatocellular carcinoma specimens and cell lines was assessed, using real-time polymerase chain reaction. Luciferase reporter assays were used to confirm CYLD as a target of miR-501-5p. The effect of miR-501-5p on cell proliferation was confirmed, using tetrazolium and colony formation assays. Gene and protein expression were examined, using real-time polymerase chain reaction and western blotting, respectively. Results MiR-501-5p was upregulated in hepatocellular carcinoma specimens and cell lines, and directly targeted the 3' untranslated region of CYLD. MiR-501-5p upregulation corresponded with a downregulation of CYLD in the same tissues and cell lines, and overexpression of MiR-501-5p decreased CYLD expression, increased expression of cyclin D1 and c-myc and promoted the proliferation of hepatocellular carcinoma cells in vitro. Conclusions This study suggests that miR-501-5p may play an important role in the development of hepatocellular carcinoma by promoting cell proliferation, and indicates that miR-501-5p may represent a novel therapeutic target for hepatocellular carcinoma.

Pre-treatment neutrophil-to-lymphocyte ratio predicts prognosis in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy.

Abstract: OBJECTIVE The aim of this study was to investigate the effect of neutrophil-to-lymphocyte ratio on the prognosis of patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. METHODS One hundred and twenty-five patients with locoregionally advanced laryngeal carcinoma (cT3-4 N0-3M0) treated with chemoradiotherapy were reviewed retrospectively. Chemoradiotherapy comprised external beam radiotherapy to the larynx (70 Gy) with three cycles of cisplatin at 3 week intervals. The survival rate was calculated using the Kaplan-Meier method, and a multivariate analysis was used to identify significant factors associated with prognosis, using a Cox proportional hazards model. RESULTS During the median (range) follow-up of 45 months, the median neutrophil-to-lymphocyte ratio was 3.02. The high neutrophil-to-lymphocyte ratio group (neutrophil-to-lymphocyte ratio > 3.0) contained 69 patients and the low neutrophil-to-lymphocyte ratio group (neutrophil-to-lymphocyte ratio < 3.0) contained 46 patients. The low neutrophil-to-lymphocyte ratio group patients had a significantly higher chemoradiotherapeutic disease control rate (86.96 vs. 69.57%, P = 0.031). Forty-six patients had a low neutrophil-to-lymphocyte ratio (<3.0) before chemoradiotherapy and their progression-free survival and 75% overall survival were significantly better than that of the high neutrophil-to-lymphocyte ratio patients (P = 0.015, P = 0.045). Multivariate analysis showed that neutrophil-to-lymphocyte ratio and N stage were independent prognostic indicators for progression-free survival (with a hazard ratio of 1.79, P = 0.003 and a hazard ratio of 1.28, P = 0.034) and overall survival (with a hazard ratio of 1.51, P = 0.029 and a hazard ratio of 1.21, P = 0.043), respectively. CONCLUSION Pre-treatment neutrophil-to-lymphocyte ratio is a useful prognostic marker in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy.

The efficacy of preoperative positron emission tomography-computed tomography (PET-CT) for detection of lymph node metastasis in cervical and endometrial cancer: clinical and pathological factors influencing it

Abstract: Objective We studied the diagnostic performance of (18)F-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography in cervical and endometrial cancers with particular focus on lymph node metastases. Methods Seventy patients with cervical cancer and 53 with endometrial cancer were imaged with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography before lymphadenectomy. We evaluated the diagnostic performance of (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography using the final pathological diagnoses as the golden standard. Results We calculated the sensitivity, specificity, positive predictive value and negative predictive value of (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography. In cervical cancer, the results evaluated by cases were 33.3, 92.7, 55.6 and 83.6%, respectively. When evaluated by the area of lymph nodes, the results were 30.6, 98.9, 55.0 and 97.0%, respectively. As for endometrial cancer, the results evaluated by cases were 50.0, 93.9, 40.0 and 95.8%, and by area of lymph nodes, 45.0, 99.4, 64.3 and 98.5%, respectively. The limitation of the efficacy was found out by analyzing it by the region of the lymph node, the size of metastatic node, the historical type of tumor in cervical cancer and the prevalence of lymph node metastasis. Conclusion The efficacy of positron emission tomography/computed tomography regarding the detection of lymph node metastasis in cervical and endometrial cancer is not established and has limitations associated with the region of the lymph node, the size of metastasis lesion in lymph node and the pathological type of primary tumor. The indication for the imaging and the interpretation of the results requires consideration for each case by the pretest probability based on the information obtained preoperatively.

Analysis of pre-operative variables for identifying patients who might benefit from upfront cytoreductive nephrectomy for metastatic renal cell carcinoma in the targeted therapy era.

Abstract: OBJECTIVE: The aim of the study is to identify pre-operative variables for selection of patients who would benefit from upfront cytoreductive nephrectomy for metastatic renal cell carcinoma. METHODS: We reviewed the medical records of 171 patients who were presented with synchronous metastatic renal cell carcinoma and who had received no systemic therapy before enrollment. Of these, 96 underwent cytoreductive nephrectomy followed by targeted therapy (cytoreductive nephrectomy group) and 75 treated with targeted therapy alone (non-cytoreductive nephrectomy group). A Cox proportional hazards regression model was used to estimate the prognostic significance of pre-operative characteristics predicting overall survival in the cytoreductive nephrectomy group. The significant variables were designated as pre-operative factors to identify patients who would benefit from cytoreductive nephrectomy. RESULTS: The median overall survival was 19.9 and 11.7 months in the cytoreductive nephrectomy and non-cytoreductive nephrectomy groups (P < 0.001). Karnofsky performance status (<80; hazard ratio 9.497, P < 0.001), hemoglobin (less than lower limit of normal; hazard ratio 1.913, P = 0.025), neutrophils (greater than upper limit of normal; hazard ratio 6.533, P < 0.001) and clinical N stage (N2; HR 2.714, P = 0.001) were independent pre-operative risk factors of mortality. Only those patients with risk factor <2 who had undergone upfront cytoreductive nephrectomy had a better median overall survival than patients who received targeted therapy alone (28.2 vs. 18.4 months, P = 0.018). CONCLUSIONS: Four pre-operative risk factors (Karnofsky performance status, hemoglobin, neutrophils and clinical N stage) were identified as suitable for selection of patients who would not benefit from undergoing cytoreductive nephrectomy.

Prognostic significance of the concomitant existence of lymphovascular and perineural invasion in locally advanced gastric cancer patients who underwent curative gastrectomy and adjuvant chemotherapy

Abstract: OBJECTIVE: In this study, we evaluated the prognostic significance of the concomitant existence of lymphovascular invasion and perineural invasion in patients with advanced gastric cancer. METHODS: A total of 206 consecutive patients with Stage II or III gastric cancer who underwent curative D2 gastrectomy and adjuvant chemotherapy from April 2004 to December 2011 were analyzed. Patients were classified into four groups according to the presence (+) or absence (-) of lymphovascular invasion and perineural invasion: lymphovascular invasion-/perineural invasion- (n = 33), lymphovascular invasion+/perineural invasion- (n = 31), lymphovascular invasion-/perineural invasion+ (n = 54) and lymphovascular invasion+/perineural invasion+ (n = 88). RESULTS: A total of 136 patients (66.0%) received 5-fluorouracil plus cisplatin adjuvant chemotherapy and 70 patients (34.0%) received TS-1. During the median follow-up period of 35.18 months, the median disease-free survival times for lymphovascular invasion-/perineural invasion-, lymphovascular invasion+/perineural invasion- and lymphovascular invasion-/perineural invasion+ were not reached at the time of analysis; however, median disease-free survival for lymphovascular invasion+/perineural invasion+ was the worst (36.73 months, P = 0.001). The median overall survival in the four groups was also not reached at the time of analysis; however, median overall survival with lymphovascular invasion+/perineural invasion+ was the poorest (P = 0.002). In a multivariate analysis, lymphovascular invasion+/perineural invasion+ was an independent prognostic factor for both disease-free survival (hazard ratio = 1.940, 95% confidence interval 1.157-3.252, P = 0.012) and overall survival (hazard ratio = 2.973, 95% confidence interval 1.561-5.662, P = 0.001). CONCLUSIONS: The concomitant existence of lymphovascular and perineural invasion has a significant prognostic impact on disease-free survival and overall survival in patients with Stage II or III gastric cancer.

A Phase III study of oral steroid administration versus local steroid injection therapy for the prevention of esophageal stricture after endoscopic submucosal dissection (JCOG1217, Steroid EESD P3).

Abstract: A randomized Phase III trial commenced in Japan in September 2014. Endoscopic local steroid injection has been commonly used and considered acceptable as the current standard treatment for the prevention of esophageal stricture after endoscopic submucosal dissection for superficial esophageal cancer. The purpose of this study is to confirm the superiority of prophylactic oral steroid administration following endoscopic submucosal dissection in terms of stricture-free survival over endoscopic local steroid injection for patients with superficial esophageal cancer. A total of 360 patients will be accrued from 35 Japanese institutions within 2.5 years. The primary endpoint is stricture-free survival, and the secondary endpoints are the number of endoscopic balloon dilations for 12 weeks after endoscopic submucosal dissection, adverse events, serious adverse events and the proportion of patients with dysphagia score ≤1 at 12 weeks after endoscopic submucosal dissection. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015064 (http://www.umin.ac.jp/ctr/index.htm).

Methodological issues in observational studies and non-randomized controlled trials in oncology in the era of big data.

Abstract: Non-randomized controlled trials, cohort studies and database studies are appealing study designs when there are urgent needs for safety data, outcomes of interest are rare, generalizability is a matter of concern, or randomization is not feasible. This paper reviews four typical case studies from methodological viewpoints and clarifies how to minimize bias in observational studies in oncology. In summary, researchers planning observational studies should be cautious of selection of appropriate databases, validity of algorithms for identifying outcomes, comparison with incident users or self-control, rigorous collection of information on potential confounders and reporting details of subject selection. Further, a careful study protocol and statistical analysis plan are also necessary.

Prevalence, course and factors associated with delirium in elderly patients with advanced cancer: a longitudinal observational study

Abstract: OBJECTIVE The aim of this study was to investigate the prevalence of delirium on admission, the course of delirium during a 2-week period after admission and factors associated with delirium on admission, among elderly patients with advanced cancer. METHODS Patients aged ≥ 65 years with incurable lung or gastroenterological cancer and the Eastern Cooperative Oncology Group Performance Status 2 or greater were continuously sampled after admission to a university hospital. Participants were evaluated for DSM-IV-TR delirium by trained psychiatrists and the delirium subtype was assessed using the Delirium Motor Subtype Scale within 4 days after admission and again 2 weeks later. In addition, we assessed associated factors with delirium on admission. RESULTS Among 73 eligible patients, complete data were available from 61 on admission and 49 after 2 weeks. Twenty-six patients (43%) met delirium criteria on admission (hypoactive: 58%, unspecified: 35%, hyperactive: 4%, mixed: 4%). Of these, 19 (73%) remained delirious 2 weeks later. Of 35 patients without delirium on admission, 21 (60%) remained delirium-free 2 weeks later and 7(20%) became delirious. Overall, 33/61 (54%) developed delirium at some point during the study. Patients receiving steroids at admission were more likely to have delirium (odds ratio = 5.0; 95% confidence interval = 1.5-16). CONCLUSIONS Given the high prevalence of the delirium, all patients with advanced cancer should be screened for delirium both on admission and regularly thereafter. In addition, medical staff should be aware that steroid use on admission is an additional indicator of elevated risk for delirium.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

Abstract: Objective: Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. Methods: All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. Results: Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand–foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7–8.1), and the overall survival rate at 1 year was 75.4% (73.5–77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis.

Quality of life in colorectal cancer patients: an Izmir Oncology Group (IZOG) study.

Abstract: Objective Determination of psychological problems will shed light on the terms of solution and provide support to patients about these problems will ensure the patients' coherence to the treatment and will enhance the benefits they receive from treatment. In this study, we aimed to determine these psychosocial problems and the interactions with each other in colon cancer patients. Methods In this study, 105 patients with colorectal cancer were included. The forms consist of sociodemographic features, Hospital Anxiety and Depression Scale, European Organization for Research on Treatment of Cancer Questionnaires Quality of Life-C30 and Golombok-Rust Inventory of Sexual Satisfaction questionnaires. Results Male patients had significantly higher European Organization for Research on Treatment of Cancer Questionnaires Quality of Life-C30 function scales and global quality-of-life scores than female patients. Golombok-Rust Inventory of Sexual Satisfaction scores of female patients were significantly higher than that of male patients. European Organization for Research on Treatment of Cancer Questionnaires Quality of Life-C30 function scales and global quality-of-life scores of the patients with high depression scores were significantly lower, conversely symptom scale scores of the patients with high depression scores were significantly higher than that of the patients with low depression scores. Patients with low anxiety scores had significantly higher European Organization for Research on Treatment of Cancer Questionnaires Quality of Life-C30 function scales and global quality-of-life scores than the patients with high anxiety scores. Symptom scale scores of the patients with high anxiety scores were significantly higher than that of the patients with low anxiety scores. The scores of Golombok-Rust Inventory of Sexual Satisfaction except premature ejaculation and vaginismus were significantly higher in patients with high anxiety scores and a significant difference was determined in touch, avoidance and anorgasm. Conclusions This study demonstrates that there is a significant association with anxiety/depression symptoms and quality-of-life scores, sexual dysfunction. Sexual dysfunction is significantly more common in patients with high anxiety and depression scores.

Biological markers of invasive breast cancer

Abstract: Biological markers for breast cancer are biomolecules that result from cancer-related processes and are associated with particular clinical outcomes; they thus help predict responses to therapy. In recent years, gene expression profiling has made the molecular classification of breast cancer possible. Classification of breast cancer by immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and Ki-67 is standard practice for clinical decision-making. Assessments of hormone receptor expression and human epidermal growth factor receptor 2 overexpression help estimate benefits from targeted therapies and have greatly improved prognoses for women with these breast cancer types. Although Ki-67 positivity is associated with an adverse outcome, its clear identification is an aid to optimal disease management. Standardization of testing methodology to minimize inter-laboratory measurement variations is a remaining issue. Multi-gene assays provide prognostic information and identify those most likely to benefit from systemic chemotherapy. Incorporating molecular profiles with conventional pathological classification would be more precise, and could enhance the clinical development of personalized therapy in breast cancer.