Hepatocellular carcinoma is the most common malignancy in liver, is also a global problem and is the fourth most commonly diagnosed cancers among men and the fourth leading causes of cancer death among both men and women in China. Liver resection or hepatic resection and radiofrequency ablation is widely accepted as a first-line surgical approach for hepatocellular carcinoma in China. However, the indications of radiofrequency ablation or hepatic resection are different and not unified in China. In this article, we review the current status of hepatic resection and radiofrequency ablation therapies in hepatocellular carcinoma management in China.
To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma.
Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells.
Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P < 0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P < 0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.00001) and visual counting (cut-off value: 28.5%; P < 0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.0001) and visual counting (cut-off value: 19.7%, P < 0. 0001).
The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.
The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer.
In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m2) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined.
Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7–12 days). Partial response was reported in four patients.
The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m2) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.
Phase I oncology trials have raised concerns that patients’ ‘unrealistic’ optimism could compromise the validity of informed consent, and that patients often participate in trials to conform to physicians’ or family members’ recommendations. We aimed to determine whether patients or families—given the same information of risk–benefit profile—are more likely to participate in Phase I trials than their physicians and whether people in family or physician situations are more likely to recommend trial participation to patients than they would want for themselves as patients.
We conducted a hypothetical vignette study with a patient–caregiver–oncologist. Three groups—725 patient–caregiver pairs recruited by 134 oncologists—were asked to assume three different roles as patients, caregivers and physicians and provided a scenario of a hypothetical patient with treatment-resistant cancer. They were asked questions regarding their intention to participate in or to recommend a Phase I clinical trial.
Acceptance rates of the trial were as follows: (a) in the patients’ role: patients (54.1), caregivers (62.3) and physicians (63.4%); (b) in the caregivers’ role: 55.6, 64.7 and 70.9%; (c) in the physicians’ role: 66.1, 70.8 and 76.1%. Patients or caregivers were not more positive to the trial than physicians. All three groups showed more positive attitudes toward the clinical trial when they assumed the role of caregiver or physician than that of patient.
Patients and caregivers seem to make as reasonable decisions as physicians; patients seem to take family members’ or physicians’ recommendation as their legitimate roles rather than as undue pressure.
Early diagnosis and treatment of cancer may contribute substantially to complete cure, but it remains unknown whether treatment of early hepatocellular carcinoma can actually result in cure. This study was performed to clarify the cancer risk of the background liver after treating early hepatocellular carcinoma.
Early hepatocellular carcinoma is defined as very well-differentiated cancer containing Glisson's triad. The cumulative incidence of classical hepatocellular carcinoma, hypervascular liver cancer detected on imaging studies, after resection of early hepatocellular carcinoma positive for anti-hepatitis C antibody (early hepatocellular carcinoma group, n = 105) was compared with that in patients with chronic liver disease positive for anti-hepatitis C antibody (control group, n = 751) and propensity score-matched patients after resection of classical hepatocellular carcinoma (classical hepatocellular carcinoma group, n = 105).
After a median follow-up of 4.8 years (range, 0.3–15.0), the cumulative incidence of classical hepatocellular carcinoma at 5 years was 56.9% (95% confidence interval, 44.2–67.7%) in the early hepatocellular carcinoma group and 70.6% (52.5–81.8%) in the classical hepatocellular carcinoma group as compared with 4.6% (2.8–6.4%) in the control group. The risk of the development of classical hepatocellular carcinoma in the early hepatocellular carcinoma group was significantly higher than that in the control group (hazard ratio, 17.5; 95% confidence interval, 12.1–25.3; P < 0.001) and significantly lower than that in the classical hepatocellular carcinoma group (hazard ratio, 0.60; 0.41–0.89; P = 0.010). However, the cumulative incidence of second primary hepatocellular carcinoma in patients with one early hepatocellular carcinoma did not differ significantly from that in patients with two or more early hepatocellular carcinoma lesions (hazard ratio, 1.50; 0.85–2.65; P = 0.157).
Treatment of early hepatocellular carcinoma cannot provide complete cure due to the substantial risk of developing classical hepatocellular carcinoma.
Preoperative chemoradiotherapy has been established as a standard treatment for locally advanced rectal cancer. It is unclear whether preoperative chemoradiotherapy is truly beneficial in the elderly patients. Our aim was to assess the impact of age on the treatment tolerance and clinical outcomes.
We retrospectively analyzed 160 consecutive patients with clinical stage T3–4, and/or lymph node positive tumors who received preoperative chemoradiotherapy from May 2003 to December 2010 at a single hospital. Treatment tolerance and outcomes were compared between patients ≥70 years (N = 56) and <70 years (N = 104).
There was no disparity in the achievement of prescribed radiation dose and dose reduction of chemotherapy between two groups. Pathologic complete response rate (15.6% vs. 16.0%) and sphincter preservation rate (91.1% vs. 95.0%; P = 0.459) were not significantly different. The 3-year disease-free survival of older vs. younger patients was 77.8% vs. 92.3% and 5-year disease-free survival was 60.0% vs. 78.6%, respectively (P = 0.023). In multivariable analysis, age was significantly associated with disease-free survival (P = 0.033) but comorbidities were not (P = 0.092). However, both age (hazard ratio, 2.331; P = 0.028) and comorbidities (hazard ratio, 2.772; P = 0.031) were significantly associated with overall survival as well as clinical stage. Anemia was the only adverse effect more prominent in older patients.
Older patients showed non-inferior compliance and equivalent pathologic complete response rates without an increased incidence of treatment complications with preoperative chemoradiotherapy. More comprehensive consideration than age alone is warranted in the decision of applying preoperative chemoradiotherapy to elderly patients with rectal cancer.
We want to review the value of 18-fluoro-deoxy-glucose positron emission tomography for response prediction of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy.
Studies were searched in Pubmed, Embase and Cochrane Library with specific search strategy. The published articles were included according to the criteria established in advance. The included studies were divided into two groups according to the time of the repeat positron emission tomography: during (Group A) or after neoadjuvant chemoradiotherapy (Group B). The studies that performed the repeat positron emission tomography after neoadjuvant chemoradiotherapy were graded Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity, specificity and diagnostic odds ratio were obtained for both groups on the basis of no-existing of threshold effect.
Fifteen studies were included in the present study. The threshold effect did not exist in both groups. The pooled sensitivity, specificity and diagnostic odds ratio were 85%, 59%, 6.82 with 95% confidence interval 76–91%, 48–69%, 2.25–20.72 in Group A. The equivalent values were 67%, 69%, 6.34 with 95% confidence interval 60–73%, 63–74%, 2.08–19.34 in Group B. The pooled sensitivity was 90% in four studies that enrolled patients with esophageal squamous cell carcinoma merely in Group B.
According to the present data, positron emission tomography should not be used routinely to guide treatment strategy in esophageal cancer patients. We speculated that positron emission tomography could be used as a tool to predict treatment response after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma.
This study is designed to evaluate the correlations of insulin-like growth factor I (IGF-I) and insulin-like growth factor I receptor (IGF-IR) expressions with the clinicopathological features and prognosis of patients with colon cancer.
From January 2010 to January 2009, tissue samples were collected from 121 colon cancer patients, 147 with colon adenoma and 63 patients with chronic diarrhea. Real-time quantitative polymerase chain reaction was used to analyze the mRNA expressions of IGF-I and IGF-IR. Immunohistochemistry was utilized to detect the protein expressions of IGF-I and IGF-IR.
The IGF-I and IGF-IR mRNA expressions in colon cancer tissues were higher than those in colon adenoma tissues and normal tissues. The positive protein expressions of IGF-I and IGF-IR in colon cancer tissues were also higher than those in colon adenoma tissues and normal tissues. The mRNA expressions of IGF-I and IGF-IR were associated with the degree of differentiation, tumor node metastasis stage and lymphatic metastasis of colon cancer. Tumor node metastasis stage, lymphatic metastasis, postoperative chemotherapy and IGF-IR protein expression were independent factors for the prognosis of colon cancer.
This study has demonstrated that overexpression of IGF-I and IGF-IR contributes to the development and progression of colon cancer.
The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC.
We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities.
Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4–36.7) and 9.1 (6.4–13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations.
This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.
Adjuvant androgen deprivation therapy is a common treatment option for prostate cancer after radical prostatectomy, especially in Asia. However, no study has investigated the oncological outcome after cessation of long-term adjuvant androgen deprivation therapy with favorable prostate-specific antigen control.
Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 56 men with pT2–4N0–1M0 prostate cancer who had received long-term (>2 years) adjuvant androgen deprivation therapy after radical prostatectomy and subsequently stopped it under a condition of continued prostate-specific antigen values <0.1 ng/mL. The oncological outcome was evaluated using biochemical recurrence, defined as two consecutive prostate-specific antigen values ≥0.2 ng/mL, as the primary endpoint. Cox proportional hazards model was used for multivariate analysis. Age at androgen deprivation therapy cessation was dichotomized as <68 years and ≥68 years, based on the most discriminatory cutoff.
Median duration of adjuvant androgen deprivation therapy was 70 months. Overall, 13 of 56 (23%) patients developed biochemical recurrence with a median follow-up period of 41 months after androgen deprivation therapy cessation. Multivariate analysis identified age at androgen deprivation therapy cessation <68 years and pN1 as independent predictors of biochemical recurrence. Predisposition of younger age to poorer survival may be related to more frequent testosterone recovery in younger men (73 vs 33%, P = 0.0299). One patient had evidence of clinical metastasis and no one died of prostate cancer.
Androgen deprivation therapy cessation would be feasible in most men who received long-term adjuvant androgen deprivation therapy after radical prostatectomy with favorable prostate-specific antigen control. Risk factors of biochemical recurrence after androgen deprivation therapy cessation included younger age at androgen deprivation therapy cessation and pN1.
We investigated chronological changes in the outcomes of patients with upper urinary tract urothelial carcinoma treated in the past two decades, during which there was an important change in treatment paradigm.
A retrospective review was conducted of 1180 urinary tract urothelial carcinoma patients who underwent radical nephroureterectomy in multicenter collaborative institutions between 1996 and 2015. The patients were divided into four groups according to the year when radical nephroureterectomy was performed, as follows: 1996–2000 (period 1; P1), 2001–05 (P2), 2006–10 (P3) and 2011–15 (P4). Variables including tumor grade, T and N categories, administration of perioperative chemotherapy and treatment outcomes were compared among the four groups.
There were 146 (12%), 312 (27%), 459 (39%) and 263 (22%) patients in the P1, P2, P3 and P4 groups, respectively. The proportion of patients harboring pT2/3 and Grade 3 tumors increased gradually from 42% (P1) to 58% (P4) and from 49% (P1) to 65% (P4), respectively. The 5-year disease-free survival rates were 74%, 74%, 73% and 75%, and the 5-year overall survival rates were 74%, 65%, 67% and 72% for the P1, P2, P3, and P4 groups, respectively. Multivariate analysis with adjustment for possible confounding factors revealed no significant differences in disease-specific survival, overall survival or intravesical recurrence-free survival among the four groups.
Despite advances in diagnostic instruments, surgery and systemic chemotherapy, the clinical outcome of urinary tract urothelial carcinoma after radical surgery has not significantly improved over the last two decades, and further research is therefore required.
Active surveillance has emerged as an alternative to immediate treatment in men with favorable-risk prostate cancer; however, consensus about defining the appropriate candidates is still lacking. To examine the factors predicting unfavorable pathology among active surveillance candidates, we assessed low-risk radical prostatectomy specimens.
This retrospective study included 1753 men who had undergone radical prostatectomy at six independent institutions in Japan from 2005 to 2011. Patients who met the active surveillance criteria were categorized depending on the pathological features of the radical prostatectomy specimens. ‘Reclassification’ was defined as upstaging (≥pT3) or upgrading (radical prostatectomy Gleason score ≥7), and ‘adverse pathology’ was defined as pathological stage ≥pT3 or radical prostatectomy Gleason score ≥4 + 3. Multivariate analysis was used to analyze the preoperative factors for reclassification and adverse pathology. The rates of reclassification and adverse pathology were evaluated by classifying patients according to biopsy core numbers.
The active surveillance criteria were met by 284 cases. Reclassification was identified in 154 (54.2%) cases, while adverse pathology in 60 (21.1%) cases. Prostate-specific antigen density and percentage of positive cores were independently associated with reclassification and adverse pathology. The rates of reclassification and adverse pathology were significantly higher among patients with <10 biopsy cores than among others. Thus, focusing on 149 patients with ≥10 biopsy cores, prostate-specific antigen density was the only independent predictor of unfavorable pathological features. The receiver operating characteristic curve analysis determines an optimal cut-off value of prostate-specific antigen density as 0.15 ng/ml2.
Prostate-specific antigen density is the most important predictor of unfavorable pathological features in active surveillance candidates.
To assess the prognostic value of perioperative changes in the neutrophil–lymphocyte ratio in patients with bladder cancer undergoing radical cystectomy.
We performed a retrospective analysis of 323 patients who had undergone radical cystectomy at our institutions. Overall survival was assessed with the Kaplan–Meier method and Cox regression analysis.
Preoperative and postoperative neutrophil–lymphocyte ratios were significantly correlated with overall survival (both P = 0.0001). Changes in perioperative neutrophil–lymphocyte ratio stratified the patients into two groups, designated favorable- and poor-risk groups, with significantly different 5-year overall survival rates (75.1% and 41.4%, respectively; P < 0.0001). Multivariate Cox regression analyses showed that the perioperative change in neutrophil–lymphocyte ratio was an independent prognostic factor for overall survival (hazard ratio 2.56, 95% confidence interval 1.75–3.73; P < 0.001). Moreover, a decrease in neutrophil–lymphocyte ratio after adjuvant chemotherapy was associated with favorable overall survival in patients with high postoperative neutrophil–lymphocyte ratio (P < 0.001), indicating that neutrophil–lymphocyte ratio may be a predictive factor for the efficacy of adjuvant chemotherapy.
Perioperative changes in neutrophil–lymphocyte ratio are significantly associated with overall survival in patients with bladder cancer undergoing radical cystectomy. Follow-up of the neutrophil–lymphocyte ratio change may be useful for the clinical management of patients after surgery.
The optimal management of clinical N2 Stage IIIA non–small cell lung cancer is still controversial. For a cure of locally advanced IIIA/N2 non–small cell lung cancer, the control of both local regions and possible distant micrometastases is crucial. Chemotherapy is generally expected to prevent distant recurrence. For local tumor control, radiotherapy or surgery has been adopted singly or in combination. If a complete resection can be safely performed, surgery remains the strongest modality for ‘eradicating’ local disease. Many retrospective studies have reported a possible survival benefit of induction treatment followed by surgery in selected patients with IIIA/N2 non–small cell lung cancer; however, randomized Phase III trials have failed to demonstrate the superiority of induction treatment followed by surgery over chemoradiotherapy, mainly because of the heterogeneity of the N2 status. IIIA/N2 non–small cell lung cancer consists of a heterogeneous group of disease ranging from microscopically single station to radiologically bulky ipsilateral multi-station mediastinal lymph node involvement. A recent definition proposed by the American College of Chest Physicians classified non–small cell lung cancer based on the N2 status, such as discrete or infiltrative type, and recommendations were made according to this N2 status, with definitive chemoradiotherapy recommended for infiltrative clinical N2 and definitive chemoradiotherapy or induction treatment followed by surgery recommended for other cases. Thus, the introduction of a multimodality treatment strategy seems to be necessary for the improved prognosis of non–small cell lung cancer patients with IIIA/N2 disease. In this review, we discuss the role of surgery and the optimal surgical management for patients with IIIA/N2 non–small cell lung cancer.
A number of promising new approaches for both local and systemic control of locally advanced non–small cell lung cancer have been examined in clinical trials, aimed at improving the patient survival. Development of better systemic therapies by adopting newer agents (such as epidermal growth factor receptor-tyrosine kinase inhibitors and immune checkpoint inhibitors) from advanced non–small cell lung cancer is mandatory. As for radiotherapy, adaptive radiotherapy and proton therapy are under investigation after the RTOG 0617 trial unexpectedly failed to show the efficacy of high-dose radiotherapy for Stage III disease. To date, no Phase III trial has clearly shown the benefit of adding surgery as a part of multimodality therapy for locally advanced non–small cell lung cancer. Such poor progress in the development of effective treatments for Stage III non–small cell lung cancer is considered to be attributable to the existence of heterogeneities in the disease characteristics, including the biological and anatomic characteristics. Constant effort via well-designed and well-conducted clinical trials is needed to decipher the heterogeneity of Stage III non–small cell lung cancer.
The aim of the study was to establish a predictive model of survival period after bone metastasis from endometrial cancer.
A total of 28 patients with bone metastasis from uterine corpus cancer were included in the study. Data at the time of bone metastasis diagnosis, which included presence of extraskeletal metastasis, performance status, history of any previous radiation/chemotherapy and the number of bone metastases, were collected. Survival data were analyzed using Kaplan–Meier methods and Cox proportional hazard models.
The most common site of bone metastasis was the pelvis (50.0%), followed by lumbar spine (32.1%), thoracic spine (25.0%) and rib bone (17.9%). The median survival period after bone metastasis was 25 weeks. The overall rate of survival after bone metastasis of the entire cohort was 75.0% at 13 weeks, 46.4% at 26 weeks and 42.9% at 52 weeks. Performance status of 3–4 was confirmed as an independent prognostic factor (Hazard ratio, 3.5; 95% confidence interval, 1.41–8.70) and multiple bone metastases tended to be associated with poor prognosis (Hazard ratio, 2.4; 95% confidence interval, 0.95–5.97). A prognostic score was calculated by adding up the number of these two factors. The 26-week survival rates after bone metastasis were 88.9% for those with a score of 0, 45.5% for those with a score of 1 and 0% for those with a score of 2 (P = 0.0006).
This scoring system can be used to determine the optimal treatment for patients with bone metastasis from endometrial cancer.
Development of hand-foot syndrome symptoms, which is a common adverse effect of several cancer chemotherapy agents, can result in patient withdrawal from treatment. Its early identification allows appropriate modification of chemotherapy regimens and can avert treatment withdrawal by minimizing the impact on quality of life and duration of discontinued therapy. We sought to develop a simple home-based self-monitoring tool to facilitate reliable early identification of hand-foot syndrome, based on the self-administered quality of life questionnaire hand-foot syndrome-14.
We modified the hand-foot syndrome-14 to create a simple tool with binary responses (‘yes’ or ‘no’) for patients to self-evaluate subjective hand-foot syndrome symptoms daily. We evaluated this tool with 187 consecutive, consenting, eligible adult patients attending four centers and treated with capecitabine, sorafenib or sunitinib for various cancers. Univariate and multivariate logistic regression analyses were used to select the items with the greatest discrimination for detecting Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 reactions, which indicate the need to modify the treatment regimen.
There were four items that were most strongly associated with Common Terminology Criteria for Adverse Events grade 2 or higher symptoms. ‘Pain associated with hand-foot syndrome’ was the most strongly associated with moderate hand-foot syndrome. For detecting moderate hand-foot syndrome symptoms, the sensitivity was 100.0%, specificity was 94.6%, positive predictive value was 82.6% and area under the curve was 0.98 by a sum of the scores of four-item self-monitoring tool with cut-off value.
We present a simple self-monitoring tool that can be used at home with high sensitivity and specificity for identifying grade 2 hand-foot syndrome. In addition, this tool might facilitate self-care.
Japan's first guidelines for parenteral fluid management for terminal cancer patients were issued in 2006. These guidelines focused on the fluid levels to administer to patients with a remaining life expectancy of 1–2 months. However, recent refinement of the concept of cachexia is prompting caregivers worldwide to rethink parenteral fluid management for terminal cancer patients.
Our objective was to develop guidelines for parenteral fluid management for terminal cancer patients with a remaining life expectancy of 1 month, a point when cachexia generally begins to severely adversely affect the body.
The Japanese Society for Palliative Medicine appointed a Guidelines Working Practitioner Group consisting of a multidisciplinary team of specialists. In response to 26 clinical questions on parenteral fluid management for terminal cancer patients, the Working Group used the Delphi method to reach consensus on the recommendability and evidence level of 89 relevant manuscripts identified through a systematic literature review. The Working Group then had an outside committee reviews the draft guidelines validity before authoring the final version.
The resulting clinically aligned guidelines contain specific recommendations (25 recommendations on physical suffering/remaining life expectancy, 10 nursing-related recommendations and 4 ethical recommendations) assessed using the Delphi method and by an outside committee.
Japanese Society for Palliative Medicine released a revised edition of the Guidelines for Parenteral Fluid Management for Terminal Cancer Patients, which are based on medical evidence and consider the pathologic features of cachexia. We recommend that caregivers carefully evaluate the clinical usefulness of the guidelines.
Guidelines for supportive care in cancer patients have recommended routine psychological screening in clinical practice, and a Japanese national project has recommended screening for depression using the Distress and Impact Thermometer. However, a previous study advocating the validity of the Distress and Impact Thermometer may have overestimated its effectiveness, as the study included already-treated patients who were not screening targets. This study re-evaluated the performance and usefulness of the Distress and Impact Thermometer using an adequate sample size and appropriate study design.
Patients were consecutively recruited at two highly specialized hospitals and three university hospitals in Japan. Inclusion criteria were (i) undergoing aggressive anti-cancer treatment, (ii) the Eastern Cooperative Oncology Group performance status score <3 and (iii) age >20 years. Patients who were receiving psychiatric treatment were excluded from the study. After completing the Distress and Impact Thermometer, patients were evaluated with the gold-standard Composite International Diagnostic Interview by researchers who were blinded to the patients’ Distress and Impact Thermometer scores.
Forty-four patients (9%) who were receiving psychiatric treatment were excluded. Of 468 subjects included in the final analysis, only 3 had current depression (0.6%). Using cutoff points recommended by the previous study, the positive and negative predictive values were 0.02 and 0.99, respectively.
Our data indicated that screening for untreated depression in cancer patients was not useful in the specific clinical settings that were studied, and such screening should be implemented in appropriate contexts. Since there are no evidence-based recommendations regarding contexts in which psychological screening is essential, further research is needed.
In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors.
This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities.
Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients.
Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.
To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer.
The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated.
Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44–87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60–66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9–32%), and the mean normal lung dose was 11.9 GyE (range: 6.0–19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01–63.6%), the mean heart V40 GyE was 13.4% (range: 1.4–29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9–48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities.
Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters.
Although the recent reclassification of histological subtypes of lung adenocarcinoma reflects disease prognosis better, the prognosis of papillary and acinar-predominant adenocarcinoma, which are highly prevalent, is heterogeneity. The present study aimed to identify the prognostic indicators for papillary and acinar-predominant adenocarcinoma.
This retrospective study included 315 consecutive patients with completely resected pathological N0 lung adenocarcinoma tumors ≤3 cm from two institutions. Tumors were classified according to histologically predominant subtypes as low-grade (adenocarcinoma in situ, minimally invasive adenocarcinoma or lepidic predominant), intermediate-grade (papillary or acinar predominant) or high-grade (solid or micropapillary predominant). Prognostic factors in intermediate-grade group were assessed among clinicopathological factors of age, gender, surgical procedure, tumor size, pleural, lymphatic and vascular invasion using Cox proportion hazards analyses.
There were 174 patients in the low-grade group, 109 in the intermediate-grade group and 32 in the high-grade group. The 3-year recurrence-free survival rates were 98.1%, 86.3% and 74.8% for these groups, respectively (P < 0.001). In the intermediate-grade group, the presence of vascular invasion was an independent prognostic factor on multivariate Cox regression analysis of recurrence-free survival (hazard ratio, 3.48; 95% confidence interval, 1.26–9.57, P = 0.01). Classification of intermediate-grade group based on vascular invasion revealed a clear division into favorable and unfavorable prognostic subgroups.
Consideration of the vascular invasion status in addition to the predominant subtype could provide a more accurate assessment of malignant aggressiveness and prognosis of patients with early-stage lung adenocarcinoma.
It has been proven that there is no survival advantage of surgery in clinical N2 non-small-cell lung cancer rather than chemoradiotherapy. Several decades ago, the results of thoracic radiotherapy for Clinical Stage III non-small-cell lung cancer were poor, and long-term survival rate was only 6%. Recent advances in combined therapy (radiotherapy and chemotherapy) have improved median survival to 15–20 months. In the Japanese registry of lung cancer surgery, the number of patients with Clinical Stage IIIA has decreased over the last decade because of the poor results of surgery alone for Clinical Stage III non-small-cell lung cancer. In contrast, survival of patients with Clinical Stage III non-small-cell lung cancer treated with surgery has improved gradually. This can be mainly attributed to the following: first, well-selected patients are treated with surgery; second, improved diagnostic imaging has produced a ‘Will Rogers phenomenon’. Similarly, concurrent chemoradiotherapy has also further improved and in recent clinical trials, the median survival time was 28–40 months. Unfortunately, recent randomized trials comparing induction chemotherapy followed by surgery, or induction chemoradiotherapy followed by surgery with chemoradiotherapy showed no significant survival advantage of surgery. Until appropriate patient selection for surgery can be shown in randomized control trials, chemoradiotherapy is the mainstream treatment for clinical N2 non-small-cell lung cancer in clinical practice.
The aim of this study was to evaluate the additional benefit of 3 Tesla magnetic resonance imaging for neurovascular bundle preservation in radical prostatectomy.
We retrospectively evaluated patients who underwent 3 T magnetic resonance imaging followed by radical prostatectomy from April 2010 through February 2014 in our university. A total of 50 patients (100 prostate sides) were included in the study. The algorithm previously we described and magnetic resonance imaging findings were considered for the decision on neurovascular bundle preservation. A tumor adjacent to the neurovascular bundle or with extracapsular extension of a posterolateral lesion of the prostate on magnetic resonance imaging was considered a contraindication for nerve-sparing radical prostatectomy. Two experienced radiologists evaluated the magnetic resonance imaging findings. Patients who received neoadjuvant hormonal therapy were excluded. All patients underwent ultrasound-guided prostate biopsy with at least 10 cores.
Overall, 60 of the 100 neurovascular bundles were preserved according to an algorithm that consisted of the clinical stage, prostate specific antigen, Gleason score and a positive biopsy core in the apex of the prostate. Considering magnetic resonance imaging findings together with the algorithm, six neurovascular bundles were not preserved. The accuracy of predicting a positive surgical margin only by the algorithm was 56 of 60 neurovascular bundle (93.3%). When adding magnetic resonance imaging, the accuracy was 50 of 54 neurovascular bundle (92.3%).
3 T magnetic resonance imaging provided no additional benefit to our algorithm for neurovascular bundle preservation.
To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma.
The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients.
The objective response rate (95% confidence interval) was 66% (50–80%) vs. 44% (36–52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6–33.2) in an updated analysis. Hypertension, diarrhea, hand–foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival.
Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation.
In Japan, flutamide had been commonly used as second-line alternative antiandrogen hormonal therapy for metastatic castration-resistant prostate cancer that relapses after initial hormone therapy before new androgen pathway inhibitors became available. In this study, we attempted to identify predictive factors for efficacy of alternative antiandrogen as second-line hormone therapy.
We identified consecutive 65 patients with metastatic castration-resistant prostate cancer who were treated with alternative antiandrogen as second-line hormonal therapy (bicalutamide to flutamide). All patients were treated with combined androgen blockade initially. We analyzed correlations between progression-free survival of alternative antiandrogen and clinicopathological characteristics, including patients’ ages, initial prostate-specific antigen levels, prostate-specific antigen levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease grades on bone scan and previous duration of prostate cancer response to combined androgen blockade.
In univariate analysis, T stage, N stage and previous duration of response to combined androgen blockade were correlated with shorter progression-free survival. We found four significant risk factors for shorter progression-free survival in multivariate analysis: initial prostate-specific antigen level, clinical N stage, extent of disease grades and previous duration of response to combined androgen blockade.
Initial prostate-specific antigen, N stage, extent of disease grades on bone scan and previous duration of response to combined androgen blockade were the significant predictors for efficacy of alternative antiandrogen as second-line hormone therapy in patients with metastatic castration-resistant prostate cancer. These findings might support that decision-making of when to start the new androgen receptor pathway inhibitors.
We conducted the present study to elucidate the clinical presentation, treatment outcomes and risk factors for the development of metachronous brain metastasis at a single progressive disease site, the so-called isolated brain metastasis, in patients with testicular germ cell tumors.
To identify metachronous brain metastasis in a timely manner, brain imaging was performed when the re-elevation of tumor markers was observed during chemotherapy, even in patients who were free from central nervous system symptoms. The medical records of 147 patients with metastatic germ cell tumors who were treated between 1991 and 2015 were retrospectively reviewed.
Eight (5.4%) of the 147 patients presented synchronous brain metastasis. Of these, five patients suffered from metachronous brain metastasis relapse. An additional nine patients developed metachronous brain metastasis during or after chemotherapy. Ten of the 14 patients with metachronous brain metastasis did not have central nervous system symptoms. Eight (57%) patients had isolated brain metastasis. Ten patients underwent multimodal treatments, predominantly chemotherapy and radiotherapy. The 3-year overall survival of all 14 patients was 34.6%, but that of the patients with isolated brain metastasis was high as 66.7%. The development of metachronous brain metastasis was associated with a choriocarcinoma element at the primary site and an human chorionic gonadotropin level of >50 000 IU/L and brain metastasis at the initial diagnosis.
In our series, we identified isolated brain metastasis in 57% of the metachronous brain metastasis patients. The monitoring of tumor markers and appropriate brain imaging are mandatory for the diagnosis of isolated brain relapse, which is associated with a higher rate of long-term survival.
The Japanese government introduced endoscopic screening for gastric cancer in 2015 as a public policy based on the Japanese guidelines on gastric cancer screening. To provide appropriate endoscopic screening for gastric cancer in Japanese communities, we developed a quality assurance manual of endoscopic screening and recommend 10 strategies with their brief descriptions as follows: (i) Formulation of a committee responsible for implementing and managing endoscopic screening, and for deciding the suitable implementation methods in consideration of the local context; (ii) Development of an interpretation system that leads to a final judgement to standardize endoscopic examination and improve its accuracy; (iii) Preparation of management and reporting systems for adverse effects by the committee for safety management; (iv) Obtaining informed consent before operation following adequate explanations regarding the benefits and harms of endoscopic screening; (v) Avoidance of frequent screenings to reduce false-positive results and overdiagnosis. As a reference, the target age group is ≥50 years, and the screening interval is 2 years; (vi) Keeping the biopsy rate within 10% as post-biopsy bleeding may occur. Before endoscopic screening, any history of antithrombotic drug usage should be checked; (vii) Nonadministration of sedation in endoscopic screening for safety management; (viii) Adherence to proper endoscopic cleaning and disinfection to reduce infection; (ix) Use of a checklist to achieve optimal program preparation when municipal governments introduce endoscopic screening; (x) Identification of the aims and roles by referring to a checklist if primary care physicians decide to participate in endoscopic screening.
The incidence of gastric cancer and the number of gastric cancer patients that a surgeon treats annually are so vastly different between countries and regions that it is not easy to define which type of gastric cancer surgery should be considered the global standard. Nevertheless, a consensus that D2 dissection is the most appropriate way to treat resectable advanced gastric cancer has arguably been reached after long-term follow-up and flexible interpretation of the Dutch D1 versus D2 trial and evidence from the Japan Clinical Oncology Group 9501 study which denied survival benefit of more extensive lymphadenectomy. After the Japan Clinical Oncology Group 9501 trial, surgeons gradually lost interest in attempting to improve survival through extended resection and instead began to expend greater resources on establishing and standardizing the technique of minimally invasive surgery and proving its oncological non-inferiority compared with the conventional approach. Laparoscopic distal gastrectomy has become an option in daily clinical practice in the Far East, and more demanding procedures such as laparoscopic total gastrectomy and laparoscopic surgery for advanced gastric cancer are currently being explored in clinical trials from the viewpoint of both safety and oncological feasibility. In addition, the high proportion of early-stage cancer in the Far East prompted surgeons to develop limited surgery such as proximal gastrectomy and pylorus-preserving gastrectomy, which warrant further evaluation regarding benefits in terms of postoperative nutritional state and/or quality of life measurements to convince the rest of the world.
The number of patients treated by proton beam therapy in Japan since 2000 has increased; in 2016, 11 proton facilities were available to treat patients. Notably, proton beam therapy is very useful for pediatric cancer; since the pediatric radiation dose to normal tissues should be reduced as much as possible because of the effect of radiation on growth, intellectual development, endocrine organ function and secondary cancer development. Hepatocellular carcinoma is common in Asia, and most of the studies of proton beam therapy for liver cancer have been reported by Japanese investigators. Proton beam therapy is also a standard treatment for nasal and paranasal lesions and lesions at the base of the skull, because the radiation dose to critical organs such as the eyes, optic nerves and central nervous system can be reduced with proton beam therapy. For prostate cancer, comparative studies that address adverse effects, safety, patient quality of life and socioeconomic issues should be performed to determine the appropriate use of proton beam therapy for prostate cancer. Regarding new proton beam therapy applications, experience with proton beam therapy combined with chemotherapy is limited, although favorable outcomes have been recently reported for locally advanced lung cancer, esophageal cancer and pancreatic cancer. Therefore, ‘chemoproton’ therapy appears to be a very attractive field for further clinical investigations. In conclusion, there are cost issues and considerations regarding national insurance for the use of proton beam therapy in Japan. Further studies and discussions are needed to address the use of proton beam therapy for several types of cancers, and for maintaining the quality of life of patients while retaining a high cure rate.
Previous studies have revealed the association of multidrug resistance with histone deacetylases inhibitors treatment in cancer cells. But little data were available for the correlation of histone deacetylases and drug-resistant-related proteins in breast cancer tissue. This study aimed to exploring the association of histone deacetylases expression with clinicopathological features, drug-resistant-related proteins, prognosis and therapeutic responses in breast cancer patients.
We performed immunohistochemistry to study the expression of HDAC1 and HDAC2 in 226 breast cancer and 34 breast fibroadenoma patients, and the expression of breast cancer resistance protein, P-glycoprotein, lung resistance protein and multidrug resistance protein in 226 breast cancer.
In breast cancer, HDAC2 expression was significantly increased than in fibroadenoma (P = 0.015), and correlated with lymph node metastasis (P = 0.002), advanced clinical stages (P = 0.016) and high histological grade (P = 0.001). Significant positive correlations were found between HDAC2 and Ki67, HDAC1 and multidrug resistance protein, HDAC2 and breast cancer resistance protein, HDAC2 and multidrug resistance protein. HDAC2 positive expression was associated with shorter overall survival (P = 0.035) of breast cancer patients. In addition, HDAC2-positive expression was significantly associated with shorter overall survival in multidrug resistance protein-positive patients (P = 0.034), but not in multidrug resistance protein-negative patients (P = 0.530). HDAC2-positive expression was associated with shorter survival in patients who received chemotherapy containing anthracyclines (overall survival, P = 0.041; disease-free survival, P = 0.084), but not in patients who received chemotherapy without anthracyclines (overall survival, P = 0.679; disease-free survival, P = 0.708).
HDAC2 overexpression correlated with the metastasis, progression and the increased Ki67, multidrug resistance protein expression in breast cancer, and HDAC2 could be a prognostic factor of breast cancer patients, especially the patients who received anthracyclines therapy.
We investigated the efficacy and safety of concurrent chemoradiotherapy using weekly low-dose docetaxel and cisplatin in patients with locally advanced nasopharyngeal carcinoma.
This was a retrospective analysis of 31 patients who were treated with this regimen from 2001 to 2014. Concurrent chemoradiotherapy consisted of radiotherapy with a total dose of 59.4–70.2 Gy plus weekly administration of docetaxel (5–10 mg/m2) and cisplatin (20 mg/m2), up to six cycles. At least two cycles of platinum-based adjuvant chemotherapy were prescribed for Stage IV and Stage III patients with partial response or stable disease after concurrent chemoradiotherapy.
Of the 31 patients, 28 (90%) completed concurrent chemoradiotherapy as planned. The overall complete response and partial response rates were 42% and 52%, respectively. Seventeen of the 21 patients who were prescribed adjuvant chemotherapy underwent it. After a median follow-up of 39.1 months for the 23 surviving patients, 9 (29%) developed locoregional recurrence or progression and 6 patients (19%) developed distant metastasis. The 3-year overall survival and progression-free survival rates were 76% and 56%, respectively. Univariate analyses revealed that clinical stage was a significant predictor of complete response, overall survival and progression-free survival. The most serious adverse events were mucositis during concurrent chemoradiotherapy and neutropenia during adjuvant chemotherapy.
This concurrent chemoradiotherapy protocol showed practical efficacy with high feasibility and acceptable toxicity. To improve the progression-free survival of patients with Stage IV disease who are treated by this protocol, changes to their treatment strategy should be considered.
To evaluate the impact of p16 expression as a surrogate marker of human papillomavirus status in oropharyngeal squamous cell carcinoma patients underwent surgery followed by postoperative radiotherapy.
We identified 126 consecutive patients with histologically confirmed, newly diagnosed oropharyngeal squamous cell carcinoma who received surgery followed by radiotherapy and had p16 expression data available. All patients were treated between 2001 and 2011. Patients with high-risk factors (positive surgical margin and/or extracapsular extension) or other risk factors (multiple positive lymph nodes, perineural/lymphovascular invasion) were offered postoperative radiotherapy with or without concurrent chemotherapy.
One hundred and four (82.5%) patients were p16-positive (p16 (+)) and 22 (17.5%) were p16-negative (p16 (–)). With a median follow-up of 56 months, patients with p16 (+) oropharyngeal squamous cell carcinoma exhibited a significantly better 5-year disease-free survival (80.7% vs. 57.6%, P < 0.001) and overall survival (84.9% vs. 59.1%, P < 0.001) than those with p16 (–) tumors. The p16 (+) oropharyngeal squamous cell carcinoma with high-risk factors (n = 64) showed no difference in disease-free survival (79.7% vs. 68.3%; P = 0.531) and overall survival (82.1% vs. 76.2%; P = 0.964) between postoperative radiotherapy and postoperative radiotherapy with concurrent chemotherapy.
Expression of p16 is a strong independent prognostic factor of survival in the postoperative setting of oropharyngeal squamous cell carcinoma. The favorable prognosis of p16 (+) oropharyngeal squamous cell carcinoma suggests a need to re-examine traditional risk stratification for determining optimal adjuvant treatment.
To evaluate the feasibility of postoperative intensity-modulated radiotherapy for head and neck cancer by investigating the patterns of failure after this therapy.
A retrospective chart review was performed.
Between March 2006 and December 2013, 122 consecutive patients with head and neck squamous cell carcinoma were treated by surgery followed by postoperative intensity-modulated radiotherapy. In regard to the site of the primary tumor, 59 (48%) patients had cancer of the oral cavity, 31 (26%) patients had cancer of the hypopharynx, 14 (11%) patients had cancer of the oropharynx, 10 (8%) patients had cancer of the larynx and 8 (7%) patients had cancer of unknown primary. The median follow-up period of the surviving patients was 54 months (range, 25–115). Concurrent chemotherapy was administered in 76 patients (62%). The median prescribed radiation dose was 66 Gy. The 3-year overall survival, progression-free survival, distant metastasis free survival and loco-regional control rates were 59%, 48%, 52.4% and 71%, respectively. Of the 122 patients, 32 developed loco-regional recurrence as the initial recurrence, including in-field recurrence in 26 patients, marginal recurrence in five patients and out-field recurrence in seven patients. Of the five patients with marginal recurrence, four have had two or more surgeries before the intensity-modulated radiotherapy and three had oral cavity cancer. Severe adverse events were not frequent, occurring at a frequency of <5%, except for mucositis. No severe toxicities associated with the flap reconstruction were observed either.
Postoperative intensity-modulated radiotherapy appears to be effective and feasible for patients with head and neck squamous cell carcinoma.
Surgical resection is employed in patients with resectable non-small cell lung cancer. Despite complete resection, recurrence is sometimes observed. Oncogenic mutations promote initiation and progression of lung cancer, and mutation status predicts treatment outcome of advanced non-small cell lung cancer; however, their impact on the recurrence patterns remains poorly understood.
We retrospectively studied 401 patients showing recurrence after complete resection of non-small cell lung cancer. Clinicopathological factors were reviewed for time to recurrence, and recurrence patterns were compared according to oncogenic status and examined according to EGFR mutational subtype.
Among 401 patients, 185 with EGFR mutation, 46 with KRAS mutation, 15 with ALK rearrangement and 155 with triple-negative mutation were identified. Multivariate analysis following univariate analyses showed that younger age, well–moderately-differentiated histology, earlier pathologic stage and presence of EGFR or ALK mutation were favorable prognostic factors for time to recurrence. Locoregional recurrence was observed in 53.3% of ALK-positive patients, being significantly common in these patients than in EGFR- and KRAS-positive patients. EGFR-positive patients mostly experienced pleural recurrence, the incidence of which was significantly higher in triple-negative mutation patients. Adrenal recurrence was observed in 7.2% of triple-negative mutation patients, but it was rarely identified in EGFR-positive patients. Among EGFR-positive patients, the incidence of brain metastases was significantly higher in L858R cohort than in Del Ex19 cohort.
In resected non-small cell lung cancer, younger age, well–moderately-differentiated histology, earlier pathologic stage and presence of EGFR or ALK mutation were favorable factors for TTR, and distinct recurrence patterns were revealed according to oncogenic mutation status and mutational EGFR subtype. Our results may provide suggestions for developing a strategy for follow-up and adjuvant therapies after resection.
Programmed death-ligand 1 is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Whereas programmed death-ligand 1 expression has been shown to be associated with the clinical response to anti-programmed death-ligand 1 antibody, the association of tumor programmed death-ligand 1 expression with clinicopathological/molecular features and with prognosis remains inconclusive in lung adenocarcinoma. We therefore examined the association of programmed death-ligand 1 expression with the clinicopathological/molecular features and prognosis of lung adenocarcinoma.
Using tissue microarrays of 268 consecutive cases of lung adenocarcinoma, we evaluated programmed death-ligand 1 expression by immunohistochemistry. We examined the association of programmed death-ligand 1 expression with clinicopathological and molecular features. We also examined the prognostic association of programmed death-ligand 1 expression, using the log-rank test as well as Cox proportional hazards regression models to compute the mortality hazard ratio (HR).
Programmed death-ligand 1 immunoreactivity (at least 5% of the tumor cells) was observed in 43 (16%) of 268 cases of lung adenocarcinoma. Programmed death-ligand 1 positivity was associated with less tumor differentiation (P < 0.0001) and EGFR wild-type status (P = 0.0008). In a multivariable logistic regression analysis, less tumor differentiation was independently associated with programmed death-ligand 1 positivity (multivariable odds ratio, 6.54; 95% confidence interval [CI], 2.37–23.3; P = 0.0001). Programmed death-ligand 1 positivity was associated with a poor prognosis for lung cancer-specific survival (log-rank, P = 0.019; HR, 1.73; 95% CI, 1.06–2.72; P = 0.030) and overall survival (log-rank, P = 0.0014; HR, 1.88; 95% CI, 1.25–2.74).
Our study demonstrated that programmed death-ligand 1 positivity in lung adenocarcinoma was associated with less tumor differentiation and EGFR wild-type status, as well as a poor prognosis.
Systematic evaluation of the association between secondhand smoke exposure and lung cancer in Japan has yet to be conducted. Here, we performed a systematic review and meta-analysis of the relationship between secondhand smoke and lung cancer in Japanese non-smokers.
Relevant studies were collected from the MEDLINE and Ichushi Web databases using a combination of search terms and Medical Subject Headings. Eligible studies were identified, and relative risks or odds ratios were extracted to calculate pooled risk estimates. This procedure was performed independently by at least two authors. Stratified analyses were carried out according to study design, publication year, and whether or not potential confounding variables were accounted for. The presence of publication bias was assessed via funnel plots.
We identified four cohort studies and five case-control studies. Quantitative synthesis was conducted only for secondhand smoke exposure in the home during adulthood. Of the 12 populations included in meta-analysis, positive secondhand smoke exposure-lung cancer associations were observed in 11, whereas an inverse association was found in the remaining 1. The pooled relative risk of lung cancer associated with secondhand smoke exposure was 1.28 (95% confidence interval: 1.10–1.48). We found no evidence of publication bias, and a significant association remained even when potentially missing studies were included (pooled relative risk: 1.26; 95% confidence interval: 1.09–1.46). The results were stable across different subgroup analyses, including by study design, publication year, and when adjusting for confounding variables.
Secondhand smoke exposure in the home during adulthood results in a statistically significant increase in the risk of lung cancer.
Although it is well known that radiotherapy for prostate cancer increases comorbid rate of secondary bladder cancer, the effect of aging and smoking with radiotherapy on incidence rate of secondary bladder cancer remains unknown. Then, this study investigated the combinational effect of external beam radiotherapy for prostate cancer and aging or smoking on comorbid rate of secondary bladder cancer.
This study included 754 Japanese patients with prostate cancer treated with radiotherapy (n = 319) and radical prostatectomy (n = 435) from 2000 through 2013. The relationship between therapeutic modality for prostate cancer as well as age or smoking status and comorbid rate of secondary bladder cancer was examined.
During the median follow-up period of 4.3 and 3.1 years, secondary bladder cancer occurred in 11 (3.4%) and 5 (1.1%) of patients with prostate cancer treated with external beam radiotherapy and radical prostatectomy, respectively. The 5-year bladder cancer-free survival rate was 97.3% in the external beam radiotherapy group and 99.4% in the radical prostatectomy group. Age (hazard ratio = 1.15, P = 0.027) and ever smoking (hazard ratio = 5.65, P = 0.011) were significant predictive factors of secondary bladder cancer incidence in the external beam radiotherapy cohort, but not in the radical prostatectomy cohort. Inversely, among men with ever smoking, but not among older men, external beam radiotherapy (hazard ratio = 9.64, P = 0.0052) was a significant risk factor of secondary bladder cancer.
Taken together, these findings suggest that smoking history might be one of criteria to choose radical prostatectomy than external beam radiotherapy for prostate cancer, and that age would not be a criterion for therapeutic selection in terms of secondary bladder cancer.
Our aim was 2-fold: first, to assess the safety of short hydration treatment for urothelial cancer; and second, to assess the resultant quality of life of patients who received the treatment.
We assessed 61 patients including 31 outpatients and 30 inpatients, who received a combination of gemcitabine and cisplatin chemotherapy with short hydration. The serum creatinine (Cr) level and the estimated glomerular filtration rate were measured to assess renal function using linear mixed model analysis. To assess quality of life, the patients were asked to respond to the Functional Assessment of Cancer Therapy-General questionnaire. The responses were then analyzed using the paired t-test.
Patients who received short hydration chemotherapy showed no significant change in serum Cr level (P = 0.423) or estimated glomerular filtration rate (P = 0.582). There was also no significant change in serum Cr level or estimated glomerular filtration rate between patients who received short hydration chemotherapy and those who received consecutive hydration chemotherapy (P = 0.154 and 0.311, respectively). In every patient, the Functional Assessment of Cancer Therapy-General total score and subscale scores both improved as a result of outpatient chemotherapy with short hydration (P < 0.01).
The short hydration gemcitabine and cisplatin regimen for patients with urothelial cancer was safe. Further, the outpatient chemotherapy was found not only to be safe, but also to have improved the patients’ quality of life.
The aim of this study was to identify the clinical predictors related to the risk of high-grade bladder cancer before first-time transurethral resection of the bladder tumor (TUR-Bt) and to externally validate the accuracy of Shapur's nomogram predicting the risk of high-grade bladder cancer in Japanese patients. As a result, episode of gross hematuria (odds ratio: 2.68, P = 0.02), larger tumor size (odds ratio: 1.89, P < 0.01) and positive urinary cytology (odds ratio: 8.34, P < 0.01) were found to be significant predictors for high-grade bladder cancer. Furthermore, the nomogram showed a high predictive accuracy in our Japanese population (area under the curve: 0.79). Clinicians will be able to predict high-grade bladder cancer using the common factors in Shapur's study and ours, such as tumor size and urinary cytology, and gross hematuria as the additional factor first identified here to decide priorities for the treatment of patients diagnosed with bladder cancer.