Phase II trial of biweekly administration with eribulin after three cycles of induction therapy in hormone receptor-positive, HER2-negative metastatic breast cancer (JACCRO BC-03).

PURPOSE: Metastatic breast cancer (MBC) is usually incurable; treatment aims to maximize patients' function and quality of life (QOL). Eribulin is a standard treatment in patients with MBC pretreated with anthracycline and taxane; however, the best administration schedule is unknown. METHODS: In this prospective phase II trial of patients with luminal MBC, we administered biweekly eribulin to patients who completed a three-cycle induction treatment. RESULTS: Sixty patients with hormone-receptor-positive and HER2-negative MBC were enrolled; 40 obtained stable disease (SD) or better efficacy after induction therapy, after which they were switched to biweekly maintenance administration. The median progression-free survival (PFS) in patients who switched to maintenance therapy was 15.21 weeks (95% CI 9.71-22.14), starting on the first day of maintenance therapy. Overall survival (OS) in patients who switched to maintenance therapy was 21.39 months (95% CI 18.89-32.89). PFS and OS in the whole population starting from the registration date were 19.00 weeks (95% CI 17.00-25.00) and 21.52 months (95% CI 16.23-24.25), respectively. PFS from the enrollment date for patients who received maintenance therapy was 25.29 weeks (95% CI 19.14-32.14). Patients who achieved complete response or partial response during induction therapy had significantly longer PFS compared to patients with SD. CONCLUSION: The efficacy of biweekly administration of eribulin at maintenance was nonsignificant. However, less frequent visits are convenient, and reduced dose intensity improves safety. Biweekly administration, besides dose reduction, could be an acceptable option for patients who are unable to maintain a standard regimen.

[Immune Checkpoint for a Kidney Cancer and Other Cancers].

Immune checkpoint inhibitors have been getting increasing attention in the field of cancer treatment, resulting in the investigation of numerous drugs and target cancers. Clinical trials of immune checkpoint inhibitors have focused on malignant melanomas and non-small cell lung cancer;however, recently, clinical trials have been carried out for other cancers. To date, 31 phase III clinical trials have been conducted for 13 types of cancer. Recently, the results of the CheckMate025 kidney cancer and CheckMate141 head and neck cancer trials have been reported. These reports showed that nivolumab significantly enhanced overall survival in comparison to that associated with an existing second-line treatment drug. Based on these results, the approval of nivolumab for use in renal cell cancer and head and neck cancer is expected in the near future. Furthermore, the results of 20 phase III clinical trials will be submitted from 2017 to 2019, expanding the approval of immune checkpoint inhibitors. However, many issues such as biomarker searches, the evaluation of antitumor effects, and the impact on medical economy remain to be resolved. In this report, we outline clinical trial trends and the future prospects for immune checkpoint inhibitors.

Post-determined emotion: motor action retrospectively modulates emotional valence of visual images.

Upward and downward motor actions influence subsequent and ongoing emotional processing in accordance with a space-valence metaphor: positive is up/negative is down. In this study, we examined whether upward and downward motor actions could also affect previous emotional processing. Participants were shown an emotional image on a touch screen. After the image disappeared, they were required to drag a centrally located dot towards a cued area, which was either in the upper or lower portion of the screen. They were then asked to rate the emotional valence of the image using a 7-point scale. We found that the emotional valence of the image was more positive when the cued area was located in the upper portion of the screen. However, this was the case only when the dragging action was required immediately after the image had disappeared. Our findings suggest that when somatic information that is metaphorically associated with an emotion is linked temporally with a visual event, retrospective emotional integration between the visual and somatic events occurs.

[Pharmacological Treatment for Bone Metastasis].

An objective of improvement of treatment outcomes of cancer is alleviation of bone metastasis that occurs in many types of cancers. Recently, the guidelines for the diagnosis and treatment of bone metastasis were published by the Japanese Society of Medical Oncology in cooperation with other groups. These guidelines are essentially evidence based for the pharmacological treatment of bone metastasis by using bone modifying agents (BMA). Cancer cells inhibit osteoblast formation and promote osteoclast proliferation. Many growth factors that are produced by the bone marrow promote osteoclast proliferation. Furthermore, many growth factors enhance the rate of cancer cell growth. These processes underlie bone metastasis. Evidence for the effectiveness of BMA for the treatment of lung cancer, breast cancer, prostate cancer, multiple myeloma, and other cancers is provided in each section of the guidelines. These guidelines also provide evidence for the suppression of skeletal related events (SRE) in lung, breast, and prostate cancers. With regard to multiple myeloma, the guidelines provide evidence for the improvement of overall survival in addition to that for suppression of SRE. Based on these evidences, the guidelines recommend aggressive treatment with BMA for bone metastasis in such cancers.

Time dilation caused by static images with implied motion.

The present study examined whether implicit motion information from static images influences perceived duration of image presentation. In Experiments 1 and 2, we presented observers with images of a human and an animal character in running and standing postures. The results revealed that the perceived presentation duration of running images was longer than that of standing images. In Experiments 3 and 4, we used abstract block-like images that imitated the human figures used in Experiment 1, presented with different instructions to change the observers' interpretations of the stimuli. We found that the perceived duration of the block image presented as a man running was longer than that of the image presented as a man standing still. However, this effect diminished when the participants were told the images were green onions (objects with no implied motion), suggesting that the effect of implied motion cannot be attributed to low-level visual differences. These results suggest that implied motion increases the perceived duration of image presentation. The potential involvement of higher-order motion processing and the mirror neuron system is discussed.

Perceived duration of plaid motion increases with pattern speed rather than component speed.

Several studies have shown that visual motion distorts perceived duration: The duration of fast-moving stimuli is judged to be longer than the same duration of stationary or slow-moving stimuli. However, it is still unclear which stages of motion processing are involved in this apparent dilation of the perceived duration. In this study, using a two-dimensional pattern motion of a plaid as a stimulus, we systematically manipulated the speed of pattern and component motions of the plaid to examine which motion information influences the perceived duration of the plaid stimuli. Experiment 1 found that perceived duration increased with pattern speed, even though component speed was constant. Experiments 2 and 3 revealed that perceived duration was unchanged, even though component speed increased, as long as the pattern speed was identical. Experiment 4 used both static and moving plaids and confirmed that the results of Experiments 1-3 reflected duration dilation, not duration compression, induced by motion. These results suggest that higher order visual processing in the middle temporal area may play an important role in motion-induced duration dilation.

Sex hormones alter Th1 responses and enhance granuloma formation in the lung.

BACKGROUND: The lung is one of the sites of granulomatous responses, which are characterized by the recruitment and organization of activated macrophages and lymphocytes. There have been several reports that have shown that some pulmonary granulomatous diseases, such as sarcoidosis and nontuberculous mycobacterial disease, are likely to be characterized by a preponderance in postmenopausal females. Although sex hormones have been shown to play an important role in the regulation of the immune system, the influence of sex hormones on pulmonary granuloma formation is still unclear. OBJECTIVES: The purpose of this study was to assess whether sex hormones are involved in granulomatous inflammation and to evaluate how sex hormones modulate this response in the lung. METHODS: Ovariectomized rats were used as an experimental postmenopausal model in which chronic pulmonary granulomatous inflammation was induced by intravenous injection of complete Freund's adjuvant. RESULTS: Histological analysis of lung tissues demonstrated enhancement of granuloma formation in the ovariectomized group. Such enhanced granuloma formation was significantly associated with generalized Th1-biased cytokine production in the bronchoalveolar lavage fluid. CONCLUSION: These results indicate that sex hormones play an important role in pulmonary granuloma formation by altering the Th1 responses.

Temporal course of position shift for a peripheral target.

When a target is presented near a leading cue stimulus, the perceived location of the target is displaced from the cue (attentional repulsion). On the other hand, a memorized target is sometimes mislocalized toward the cue (attentional attraction). The present study aimed at clarifying the temporal relationship between attentional repulsion and attentional attraction. We used a relative judgment task wherein observers judged whether the horizontal location of the target circle was displaced leftward or rightward from the location of a vertically separated probe disk. In Experiments 1 and 2, the stimulus-onset asynchrony (SOA) between the target and the probe was manipulated from 0 ms to 2000 ms. Repulsive and attractive position shifts were observed at short and long target-probe SOAs, respectively. In Experiment 3, we found that both the cue-target SOA and the target-probe SOA governed the repulsion and attraction in different ways. The results suggest that attentional repulsion and attentional attraction occur at different visual processing stages.

[Pattern goodness and perceptual organization].

The present study examined the relation between the manner of perceptual organization and pattern goodness. We presented regularly arranged dot patterns (Experiment 1) and randomly arranged dot patterns (Experiment 2). In both experiments, the participants were asked to evaluate the goodness of the patterns using a 7-point scale and to encircle the dots in the manner that the participants had organized them. The results for both experiments showed that patterns organized with fewer groups were rated as better than patterns organized with more groups, despite having the same structure. These results indicate that the variation in pattern goodness which is not explained by the physical structure of the pattern is explained by the manner of perceptual organization used by the observer.

Risk Profiling of Cancer Treatment-Related Cardiovascular Disorders in Breast Cancer Patients Who Received Adjuvant Chemotherapy With Trastuzumab.

Background: The prognosis of cancer survivors has dramatically improved, but effective strategies for cancer treatment-related cardiovascular disorders (CTRCD) remain to be elucidated in the emerging field of cardio-oncology. In this study, we investigated risk factors for CTRCD in breast cancer patients treated with trastuzumab. Methods and Results: We performed a retrospective analysis of 141 consecutive women who received adjuvant trastuzumab, and underwent baseline (BL) and follow-up (FU) echocardiography at Juntendo University between April 2010 and December 2016. The major concomitant treatment was anthracyclines in 94% and radiotherapy in 53%. During the median treatment period of 11 months, there were 22 (15.6%) cardiology consultations, 3 (2.1%) treatment interruptions with irreversible CTRCD, and no deaths. Left ventricular ejection fraction (LVEF) was decreased from a median 67.5% (BL) to 63.4% (FU; P<0.0001), with reduced LVEF noted in 26.2% at FU<90%BL, in 13.5% at FU

Audiovisual tau effect.

This study investigated how spatial intervals between successive visual flashes are influenced by the temporal intervals between auditory pure tones presented concurrently with the flashes. Three successive visual flashes defined two spatial intervals with different extents as well as two equal temporal intervals. The onsets of the first and third tones were temporally aligned with those of the first and third flashes, while the onset of the second tone was temporally offset to that of the second visual flash, resulting in shorter or longer temporal intervals between pairs of tones. Observers judged which of the first or second spatial intervals between flashes was shorter. The results showed that the shorter temporal interval between tones caused underestimation of the spatial interval between flashes. On the other hand, stimuli without the first and third tones did not result in underestimation of spatial intervals between flashes. These results indicate an audiovisual tau effect, which is triggered by a constant velocity assumption applied to moving objects defined by more than one modality.

New motion illusion caused by pictorial motion lines.

Motion lines (MLs) are a pictorial technique used to represent object movement in a still picture. This study explored how MLs contribute to motion perception. In Experiment 1, we reported the creation of a motion illusion caused by MLs: random displacements of objects with MLs on each frame were perceived as unidirectional global motion along the pictorial motion direction implied by MLs. In Experiment 2, we showed that the illusory global motion in the peripheral visual field captured the perceived motion direction of random displacement of objects without MLs in the central visual field, and confirmed that the results in Experiment 1 did not stem simply from response bias, but resulted from perceptual processing. In Experiment 3, we showed that the spatial arrangement of orientation information rather than ML length is important for the illusory global motion. Our results indicate that the ML effect is based on perceptual processing rather than response bias, and that comparison of neighboring orientation components may underlie the determination of pictorial motion direction with MLs.

[Efficacy of gefitinib according to smoking status in non-small cell lung cancer patients].

Gefitinib is a molecular targeting agent and more effective in patients with characteristics of oriental ethnicity, female gender, adenocarcinoma and non-smokers. It is sometimes effective in smokers, but few papers have focused on the association between efficacy and smoking history. The aim of this study is to evaluate the association between efficacy of gefitinib and patients' characteristics, especially smoking history. Between July 2002 and September 2006, 89 patients were diagnosed as non-small cell lung cancer and administered gefitinib. Eighty of them were assessable for efficacy and toxicity of gefitinib. Response rate was 16.2% and 39.6%(p=0.031)in smokers and non-smokers. Survival was statistically greater in non-smokers. In smokers, there are more cases which showed response to gefitinib with a lower smoking index and longer duration after smoking cessation. Smoking index and duration after smoking cessation should be considered when gefitinib is administered or EGFR mutation analysis is conducted in patients with non-small cell lung cancer.

Overcoming the Adverse Effects of Everolimus to Achieve Maximum Efficacy in the Treatment of Inoperable Breast Cancer: A Review of 11 Cases at Our Hospital.

Everolimus is an effective treatment for advanced and/or metastatic breast cancer, especially in hormone receptor-positive cases. However, adverse events have prevented considerable numbers of clinicians from using this drug. Herein, we reviewed our clinical experiences and endeavored to identify patients in whom the benefits of everolimus treatment would outweigh these adverse events. If measures were available to prevent or minimize adverse effects prior to treatment, everolimus would be a more widely applicable drug. This retrospective study involved 11 patients in whom nonresectable or recurrent breast cancers were treated with everolimus between April 2014 and January 2016. Two patients achieved a partial response (PR) and 4 showed stable disease (SD) (1 showed long SD, i.e., > 24 weeks). The response rate was 18%, and the clinical benefit rate (PR + long SD) was 27%. Regarding adverse events, interstitial pneumonia (grade 3) developed in 3 patients (18%), necessitating treatment discontinuation. When using everolimus, it may be important to select suitable patients for whom this treatment can be continued with sufficient control of adverse events. Herein, we provide information relevant to the clinical use of everolimus based on our daily practice experiences with this agent.

Subjective disappearance of a target by flickering flankers.

This study examined the subjective disappearance of a visual object induced by a neighboring flickering ring (Experiments 1 and 2), a set of four flickering dots (Experiment 3), and apparent motion (Experiment 4) as flickering flankers. Observers were asked to report whether a target disappeared during 10 s of stimulus presentation. We used the proportion of disappearance as a measure of performance. Interestingly, subjective disappearance was rarely observed when flickering flankers were presented with a separation of less than 0.5 degrees from the target. However, disappearance was observed when dynamic random-dot patterns were presented with a separation of less than 0.5 degrees from the target border (Experiment 5). Our results indicate that the flicker of flankers near the target disturbs target adaptation or attentional inhibition, causing persistent target representation in higher-order object selection, and resulting in non-disappearance of the target.

Trypophobic Discomfort is Spatial-Frequency Dependent.

Clusters of holes, such as those in a lotus seedpod, induce trypophobic discomfort. Previous research has demonstrated that high-contrast energy at midrange spatial frequencies in images causes trypophobic discomfort. The present study examined the effects on discomfort of eliminating various spatial frequency components from the images to reveal how each spatial frequency contributes to the discomfort. Experiment 1 showed that eliminating midrange spatial frequencies did not affect trypophobic discomfort, while Experiment 2 revealed that images of holes that consisted of only high-spatial frequencies evoked less discomfort than other images and that images containing only low or midrange spatial frequencies induced as much trypophobic discomfort as did the original images. Finally, Experiment 3 found that participants with a high level of the trypophobic trait experienced stronger discomfort from the original images and the images containing only low or midrange spatial frequencies than participants with a low level of the trypophobic trait. Our findings thus suggest that trypophobic discomfort can be induced by middle and low spatial frequencies.

Cross-cultural validity of the theory of planned behavior for predicting healthy food choice in secondary school students of Inner Mongolia.

AIMS: Unhealthy eating behavior is a serious health concern among secondary school students in Inner Mongolia. To predict their healthy food choices and devise methods of correcting unhealthy choices, we sought to confirm the cross-cultural validity of the theory of planned behavior among Inner Mongolian students. MATERIALS AND METHODS: A cross-sectional study, conducted between November and December 2014. Overall, 3047 students were enrolled. We devised a questionnaire based on the theory of planned behavior to measure its components (intentions, attitudes, subjective norms, and perceived behavioral control) in relation to healthy food choices; we also assessed their current engagement in healthy food choices. RESULTS: A principal component analysis revealed high contribution rates for the components (69.32%-88.77%). A confirmatory factor analysis indicated that the components of the questionnaire had adequate model fit (goodness of fit index=0.997, adjusted goodness of fit index=0.984, comparative fit index=0.998, and root mean square error of approximation=0.049). Notably, data from participants within the suburbs did not support the theory of planned behavior construction. Several paths did not predict the hypothesis variables. However, attitudes toward healthy food choices strongly predicted behavioral intention (path coefficients 0.49-0.77, p<0.01), regardless of demographic characteristics. CONCLUSION: Our results support that the theory of planned behavior can apply to secondary school students in urban areas. Furthermore, attitudes towards healthy food choices were the best predictor of behavioral intentions to engage in such choices in Inner Mongolian students.

Effect of telling patients their "spirometric-lung-age" on smoking cessation in Japanese smokers.

BACKGROUND: Cigarette smoking remains a significant public health problem. However, current treatment programs have not yet succeeded in sufficiently reducing smoking rates. The study aimed to examine whether patients' recognition of "spirometric-lung-age (SLA)" estimated from spirometry data prompts smoking cessation. METHODS: From December 2010 to September 2011, participating smokers were prospectively enrolled into the standardized smoking cessation program (Visits 1-5 for 12 weeks) and assigned single-blindly to either SLA assessment or control groups. The SLA group was informed of the estimated age of their lungs from spirometry analysis and given an opportunity to recognize the difference from their actual chronological age, whereas the control group was not. The primary calculation of outcome was the smoking quit rate on Visit 5, whereas the secondary end-point was the proportion of patients who remained abstinent 1 year later. RESULTS: One hundred and twenty-six Japanese smokers (88 males) participated and were randomly assigned to the SLA group (n=52) or the control group (n=74). The smoking quit rate on Visit 5 was similar in the SLA assessment group and control group (59.6% vs. 41.9%; P=0.0700). However, the proportion of patients who remained abstinent 1 year later was similar in both groups (78.6% vs. 69.0%; P=0.5497). Multivariate logistic regression analysis after adjusting baseline characteristics demonstrated that telling patients their SLA, the use of varenicline, and age were significantly associated with smoking quit rate on Visit 5 whereas only age was associated with remaining abstinent 1 year later. CONCLUSIONS: Telling patients their SLA can become a useful tool prompting smoking cessation among Japanese smokers although other factors such as pharmacotherapy and age also influence the cessation of smoking.

Prognostic factors in patients with inoperable non-small cell lung cancer--an analysis of long-term survival patients.

A survival benefit of patients with inoperable non-small cell lung cancer has been reported since a development of new therapeutic agents in the 1990's. However, multivariate analyses of patients have not been evaluated. The aim of this study is to identify prognostic factors in the long-term survivors who had been treated with chemotherapy using these new agents and/or radiotherapy. A retrospective study and clinical analysis of 121 inoperable nonsmall cell lung cancer patients were conducted. Fifteen cases (male: 9, female: 6) with a survival of more than 2 years were revealed. Regarding clinical variables between the 15 cases and others, an early nodal (N) status, a high serum protein level, a good performance status (PS) and those having first-line chemotherapy or radiotherapy were all identified as significant prognostic factors for the long-term survivors. Multivariate analyses also revealed that an early N status, a good PS, female gender and chemotherapy and/or radiotherapy were associated with the long-term survivors. These results suggest that patients with inoperable non-small cell lung cancer should be considered for appropriate treatments including new chemotherapeutic agents.

[A case of non-small cell lung cancer accompanied with hemorrhage after chemotherapy including gemcitabine].

A 51-year-old man underwent left upper lobectomy due to pulmonary adenocarcinoma (cT2N1M0, stage IIB) in August, 2003. Since he turned out pT2N3M0 stage IIIB, he received combination chemotherapy with carboplatin and gemcitabine. During a second course chemotherapy, he was admitted again because of dyspnea and the deterioration of diffuse interstitial shadows in both lungs. He was treated with various antibiotics and corticosteroids. Unfortunately, he could not recover. An autopsy was performed. Microscopic features of the lung revealed diffuse alveolar damage and pulmonary hemorrhage. In this case, pulmonary hemorrhage should be considered as a complication of gemcitabine-induced lung injury.