Kiyohiro Sakai

Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification

Background:MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification.Methods:With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays.Results:We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling.Conclusion:Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification.

Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy

BACKGROUND The EML4-ALK fusion oncogene represents a recently identified molecular target in a subset of patients with non-small-cell lung cancer (NSCLC). Limited data have been available, however, on the outcome of first-line platinum-based chemotherapy in patients with EML4-ALK-positive advanced NSCLC who have not been treated with an ALK kinase inhibitor. PATIENTS AND METHODS The efficacy of platinum-based chemotherapy was compared between patients with advanced nonsquamous NSCLC who harbor EML4-ALK and those who harbor EGFR mutations and those with neither molecular abnormality. RESULTS Among 200 patients with advanced nonsquamous NSCLC, 18 (9.0%) were positive for EML4-ALK, 31 (15.5%) harbored EGFR mutations, and 151 (75.5%) were wild type for both abnormalities. Platinum-based combination chemotherapy showed similar efficacies in the EML4-ALK, EGFR mutation, and wild-type cohorts in terms of response rate and progression-free survival, and overall survival in the EML4-ALK cohort closely resembled that in the wild-type cohort. Within the EML4-ALK cohort, patients with variants 1 or 3 of the fusion gene were predominant and did not appear to differ in their sensitivity to the platinum-based regimens. CONCLUSION Patients with EML4-ALK-positive advanced NSCLC manifest an aggressive clinical course similar to that of those with wild-type tumors if the effective targeted therapy is not instituted.BACKGROUND The EML4-ALK fusion oncogene represents a recently identified molecular target in a subset of patients with non-small-cell lung cancer (NSCLC). Limited data have been available, however, on the outcome of first-line platinum-based chemotherapy in patients with EML4-ALK-positive advanced NSCLC who have not been treated with an ALK kinase inhibitor. PATIENTS AND METHODS The efficacy of platinum-based chemotherapy was compared between patients with advanced nonsquamous NSCLC who harbor EML4-ALK and those who harbor EGFR mutations and those with neither molecular abnormality. RESULTS Among 200 patients with advanced nonsquamous NSCLC, 18 (9.0%) were positive for EML4-ALK, 31 (15.5%) harbored EGFR mutations, and 151 (75.5%) were wild type for both abnormalities. Platinum-based combination chemotherapy showed similar efficacies in the EML4-ALK, EGFR mutation, and wild-type cohorts in terms of response rate and progression-free survival, and overall survival in the EML4-ALK cohort closely resembled that in the wild-type cohort. Within the EML4-ALK cohort, patients with variants 1 or 3 of the fusion gene were predominant and did not appear to differ in their sensitivity to the platinum-based regimens. CONCLUSION Patients with EML4-ALK-positive advanced NSCLC manifest an aggressive clinical course similar to that of those with wild-type tumors if the effective targeted therapy is not instituted.

Early palliative intervention for patients with advanced cancer.

BACKGROUND Early palliative intervention in advanced cancer patients with metastatic non-small-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. OBJECTIVE We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. METHODS Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for <7 days (late referral group, 64 patients) and those who experienced outpatient services for ≥7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. RESULTS Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P < 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P = 0.010) and 16.5 and 20.9 months (P = 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P = 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P = 0.018) in non-small-cell lung cancer. CONCLUSIONS The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted.

Gender differences in cancer-related distress in Japan: a retrospective observation study

BackgroundCancer care is currently the most important medical issue in Japan. Total pain of cancer patients consists of a combination of four factors: physical, psychological, social distress, and spiritual pain. Previous studies showed female cancer patients ask for more psychological support and seem to suffer different types of distress compared with male patients, for example, appearance-related symptoms. However, other factors of cancer distress related to gender have not been defined comprehensively. The aim of this study is to clarify the gender differences in cancer distress types in order to elucidate the measures that should be taken in Japan to improve the quality of whole cancer care based on gender-based medicine.MethodsThe data of new patients who had visited the psycho-oncology outpatient service of Kinki University Hospital during the period of May 2013 to October 2015 were collected. Demographic factors and all assessed items were extracted from the patients’ medical charts retrospectively. Based on an inquiry of cancer patients in 2010, each item representing the four factors of “total pain” of cancer patients was chosen, i.e., physical distress (pain, changes in appearance), psychological distress (anxiety, depression), social distress (family problems, job-related problems), and spiritual pain; together with sexuality issues, and answers were analyzed. Hospital Anxiety Depression Scale (HADS) was used for the assessment of psychological distress. Chi-square test and Fisher’s exact test were performed for gender differences in the cancer distress types. Pearson’s analysis and multiple logistic regression analysis were performed for the association of gender with each item.ResultsThe data of 101 cancer patients were analyzed and there were more female patients than male patients (female: male ratio = 71:30). Female cancer patients were more likely to suffer from psycho-social issues such as changes in appearance, family problems and sexuality issues than male patients, and male patients were more likely to have spiritual pain.ConclusionsThere were gender differences in the distress types of cancer patients. In order to improve the quality of whole cancer care, more intensive intervention by medical professionals and social support is needed from the viewpoint of gender-based medicine and psycho-oncology.

Psychological Problems for Non-Japanese Speaking Patients in Japan

The psychological problems of non-Japanese people are becoming more outstanding, in accordance with the increase of foreign nationals in Japan. Five illustrative cases of English-speaking patients were analyzed, from the viewpoint of psychosomatic medicine. The most common psychiatric disorders were adjustment disorders, because of the cultural differences and language barriers.

Prospective replication study implicates the catechol-O-methyltransferase Val158Met polymorphism as a biomarker for the response to morphine in patients with cancer

Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680; p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naïve patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naïve and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.

P3.01-96 Clinical Characteristics of Non–Small Cell Lung Cancer Harboring Mutations in Exon 20 Of EGFR or HER2

higher incidence of cough (p 1⁄4 0.001) and hemoptysis (p < 0.0001) in the bevacizumab-based arm, pain in the pemetrexed arm (p 1⁄4 0.007), and alopecia in the other treatments arm (p < 0.0001) was observed during treatment. A significantly higher incidence of hemoptysis in the bevacizumab-based arm (p < 0.0001) and alopecia in the other treatments arm (p < 0.0001) was seen at the end of first-line treatment. Conclusion: Bevacizumab-based regimens resulted in improved treatment response and short-term survival rate, but not in improved OS. An increased, albeit acceptable, toxicity was also observed among bevacizumab-treated patients as compared to those treated with pemetrexed monotherapy.

Expectation of a Decrease in Pain Affects the Prognosis of Pain in Cancer Patients: a Prospective Cohort Study of Response to Morphine

PurposeCancer pain is a multidimensional experience that includes physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Few prospective studies have examined the relationship between a patient’s expectation of pain improvement and the pain prognosis. The aim of this prospective study was to investigate whether patients’ expectation to pain reduction was associated with pain intensity after morphine treatment in opioid treatment-naïve patients with various types of cancer.MethodsThe subjects were patients scheduled for cancer pain treatment with morphine who were taking nonsteroidal anti-inflammatory drugs daily. Morphine treatment was performed according to the standard method, including titration (NCCN Guidelines™, Adult Cancer Pain). Simple regression analysis was performed between pain intensity numerical rating scale (NRS) (day 8) as the dependent variable, expectation of pain decrease NRS (day 1), tumor types, and the following covariates as independent variables: patients’ characteristics such as age, gender, PS (day 1), genotype of catechol-O-methyltransferase, total scores of Hospital Anxiety and Depression Scale (day 1), and pain intensity NRS (day 1). Multiple regression analysis was performed using forced entry methods with pain intensity NRS (day 8) as the dependent variable, and expectation of pain decrease NRS (day 1) and the covariates as independent variables that had a p value <0.05 in the simple regression models.ResultsA total of 100 patients with baseline data were included, and 97 patients (51% female) met the inclusion criteria. Patients with a high expectation of pain decrease NRS had a significantly lower pain intensity NRS (day 8) (p = 0.001).ConclusionNon-pharmacological factors such as expectations for pain treatment could also be important factors to treat cancer pain, which might be associated with communication skills in physicians.

Clinical outcome of node‐negative oligometastatic non–small cell lung cancer

The concept of “oligometastasis” has emerged as a basis on which to identify patients with stage IV non–small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node‐negative oligometastatic NSCLC.

The physical and psychological problems of immigrants to Japan who require psychosomatic care: a retrospective observation study

BackgroundAs the number of immigrants to Japan increases, the health problems of foreign nationals also have an increasing impact on Japanese medical institutions. The aim of this study was to clarify the Japan–specific health problems related to both the physical and psychological symptoms of foreign nationals from the viewpoint of psychosomatic medicine. The second aim was to clarify the measures that should be taken in Japan and similar countries where immigration may still be considered less than common.Case PresentationThe study period was from June 2004 to May 2015. The data of non-Japanese patients who had visited the Department of Psychosomatic Medicine, Kinki University Hospital and its branches, Sakai Hospital and Nihonbashi Clinic, were collected. All patients were aged 16 years or over. Multiple factors, such as age, sex, nationality, length of stay, marital status, employment status, level of Japanese proficiency, clinical symptoms, physical and psychiatric diagnosis, psycho-social factors and therapy were retrospectively analyzed from the medical charts of 20 non-Japanese patients. Cases were divided into two groups; early onset and late onset cases. This study showed that multiple factors related to the health problems of non-Japanese patients were combined and had a mutual influence, however, they can be summarized into two important clinical observations. These are 1) cultural differences, and 2) language barriers related to both the physical and psychological symptoms of non-Japanese patients from the viewpoint of psychosomatic medicine.ConclusionsFuture efforts should focus on sensitizing health care professionals in Japan to the psychosomatic problems of non-Japanese patients as well as on facilitating medical systems with services such as medical professional interpreters and liaison-consultation models. It is essential to take measures against language barriers and to promote the field of transcultural psychiatry and psychosomatic medicine in Japan. In addition, the Japanese government should introduce a more comprehensive social support system for non-Japanese people.