Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Patient-generated health data collection using a wearable activity tracker in cancer patients-a feasibility study.

PURPOSE: Incorporation of patient-generated health data (PGHD) into clinical research requires an investigation of the validity of outcomes and feasibility of implementation. This single-arm pilot trial investigated the feasibility of using a commercially available activity tracking wearable device in cancer patients to assess adherence to the device and real-time PGHD collection in a clinical research setting. METHODS: From July to November 2017, enrolled adult patients were asked to wear a wristband-style device. Brief Fatigue Inventory (BFI) and MD Anderson Symptom Inventory (MDASI) were assessed at baseline and on day 29. Furthermore, 29-day Pittsburgh Sleep Quality Index, global impression of the devices, and NCI CTCAE v4 were evaluated. RESULTS: Of 30 patients (mean age, 58.6 years; male, 21 [70%]), 15 (50%) and 11 (36.7%) had gastrointestinal and lung cancer, respectively, and 27 (90%, 95% CI: 0.74-0.98) were well adhered (> 70%) to the device for 28 days. The mean adherence was 84.9% (range: 41.7-95.2%). More frequent PGHD synchronization tended to show better device adherence, with moderate correlation (r = 0.62, 95% CI: 0.33-0.80, p < 000.1). CONCLUSIONS: The feasibility of using a wearable activity tracker was confirmed in cancer patients receiving chemotherapy for a month. For future implementation in clinical trials, there is a need for further comprehensive assessment of the validity and reliability of wearable activity trackers. TRIAL REGISTRATION: This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN: UMIN000027575.

Identification of sialylated glycoproteins in Doxorubicin-treated hepatoma cells with glycoproteomic analyses.

Sialylation is one of the most important types of glycosylation involved in carcinogenesis and establishment of cancer stemness. We previously showed that increased sialylation is a characteristic glycan change in cancer stem cells (CSCs) from hepatocellular carcinoma. However, the identities of glycoproteins targeted for sialylation remain unknown. In the present study, we identified glycoproteins targeted for sialylation in doxorubicin (DXR)-treated hepatocarcinoma cell line, Huh7, using glycoproteomic analyses. Since CSCs constitute a small subset of cells within carcinoma cell lines, it is difficult to identify sialylated proteins using general glycoproteomic strategies. It is known that treatment with anticancer drug can condense CSCs, we used DXR to concentrate CSCs. In DXR-treated Huh7 cells, isobaric tag for relative and absolute quantitation (iTRAQ) analysis identified 17 sialylated glycoproteins. Most of the identified glycoproteins were cancer-associated proteins. Furthermore, two proteins of approximately 70 kDa were detected using Sambucus sieboldoana agglutinin (SSA) blot analysis and identified as beta-galactosidase and alpha-2-HS-glycoprotein (fetuin-A) by SSA precipitation followed by liquid chromatography-tandem mass spectrometry analyses. Sialylation levels of fetuin-A were increased in DXR-treated Huh7 cell lysates. These changes in sialylation of glycoproteins might be involved in the establishment of cancer stemness.

Preferences for pharmacist counselling in patients with breast cancer: a discrete choice experiment.

With the shift of a large proportion of cancer chemotherapy recipients to ambulatory care, the role of hospital pharmacists has changed, and their provision of information is essential care for cancer patients. There is little research on pharmacist-patient relations, particularly about pharmacist counselling, in Japan. To meet patients' needs, pharmacist counselling should be optimized. Here, breast cancer patients' preferences for pharmacist counselling were assessed using a discrete choice experiment. Bayesian nonlinear optimal methodology was employed to obtain six attributes (attitude of pharmacist, quality of information, explanation of side effects, frequency of pharmacist counselling before starting chemotherapy, cost of pharmacist counselling, and follow-up with the pharmacist after starting chemotherapy) of two to three levels each. The attributes and levels were used to create 12 hypothetical scenarios that were divided into two questionnaires of six choice sets each. Two hundred eighty participants were randomly assigned to complete one of these questionnaires (blocks). Attributes were analyzed by conditional logit model to determine significant predictors of patient preferences. The responses of 278 patients to 1667 scenarios were analyzed. Attitude of pharmacist, quality of information, cost of pharmacist counselling, and follow-up with the pharmacist after starting chemotherapy were significant predictors of patient preferences, with quality of information receiving the highest priority. Thus patients receiving pharmacist counselling before starting chemotherapy prefer to interact with a pharmacist with a friendly, interested attitude who provides individualized information. Further research is needed to elucidate the information that Japanese patients consider most important and to enhance pharmacist-patient communication.

Pembrolizumab-induced secondary adrenal insufficiency due to adrenocorticotrophic hormone deficiency in a patient with non-small-cell lung carcinoma: a case report.

BACKGROUND: Pembrolizumab can cause immune-related adverse events such as adrenal insufficiency (AI). However, there is no consensus regarding appropriate monitoring of adrenal function during subsequent chemotherapy in patients who have received immune checkpoint inhibitors (ICIs) such as pembrolizumab. CASE PRESENTATION: In this report, we discuss the case of a 60s-year-old male patient with non-small cell lung cancer receiving chemotherapy who developed secondary AI due to adrenocorticotrophic hormone (ACTH) deficiency 8 months after the discontinuation of pembrolizumab, which was 17 months after the initiation of pembrolizumab immunotherapy. After 5 months of chemotherapy, he developed fever and diarrhoea, after which chemotherapy was discontinued. Thereafter, he was hospitalised owing to the development of general fatigue and anorexia. Although cortisol and ACTH levels were not measured during chemotherapy, they were measured before hospitalisation, and secondary AI was suspected. After admission, a detailed endocrine workup was performed, and the patient was diagnosed with secondary AI due to ACTH deficiency. Treatment with hydrocortisone was initiated, which markedly improved his general fatigue and anorexia. The patient showed no evidence of progressive disease 9 months after the discontinuation of pembrolizumab. CONCLUSIONS: Although rare, the possibility of AI should be considered in patients who have received ICIs when nonspecific symptoms develop during or after subsequent chemotherapy, and measurements of endocrine function (including cortisol and ACTH levels) should be performed.

Psychological Barriers to the Use of Opioid Analgesics for Treating Pain in Patients With Advanced Recurrent Cancer: A Multicenter Cohort Study.

Background: We aimed to gain insight into psychological barriers toward initiation of strong opioid analgesic use in patients with advanced recurrent cancer. Methods: This study included 46 patients who were prescribed with opioid analgesics for advanced recurrent cancer. The primary outcome was psychological barriers assessed using the Japanese version of the Barriers Questionnaire-II (JBQ-II). The secondary outcomes were psychological changes and pain relief one week after the induction of strong opioid analgesics. Results: The mean age of participants was 63.6 years. Furthermore, 26.1% had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥3. The mean JBQ-II total score was 1.97 (95% confidence interval: 1.75-2.19). At the initiation of opioid therapy, there was no difference in the total scores between the baseline and one week later. Nevertheless, there was a significant difference in the subscale "disease progression" score (mean 2.97 vs. 2.59, difference in means 0.38, standard error 0.16, p = 0.026). Personalized Pain Goal (PPG) was achieved in about half of the participants, and a trend toward a higher score in the subscale "harmful effects" (concern about adverse events) was observed in those who did not achieve PPG. Conclusion: This study showed that patients with advanced recurrent cancer have psychological barriers to opioid induction. The relationship between the presence of psychological barriers before and after induction of opioid analgesics and the speed of pain improvement was determined. The results may provide fundamental information for prospective intervention studies to develop individualized education programs for patients with psychological barriers to opioids.Clinical Trial Registration Number UMIN000042443.

Development and validation of the Japanese version of the Decisional Conflict Scale to investigate the value of pharmacists' information: a before and after study.

BACKGROUND: The information provided in patient-centered care and shared decision-making influences patients' concerns and adherence to treatment. In the decision-making process, patients experience decisional conflict. The Decisional Conflict Scale (DCS) is a 16-item, self-administered questionnaire consisting of 5 subscales developed to assess patients' decisional conflict. This study aimed to develop the Japanese version of the DCS and to clarify the influence of the information provided by pharmacists' on decisional conflict among patients with cancer. METHODS: We developed the Japanese version of the DCS by using the forward-backward translation method. One hundred patients who were recommended a new chemotherapy regimen were recruited. The psychometric properties of the Japanese DCS, including internal consistency, convergent validity, discriminant validity, and construct validity, were examined. We assessed the decisional conflict of patients before and after the pharmacists' provision of information. RESULTS: Ninety-four patients, predominately female, with an average age of 58.1 years were sampled. The scores on the 5 subscales of the DCS showed high internal consistency (Cronbach's alpha = 0.84-0.96). Multi-trait scaling analysis and cluster analysis showed strong validity. The mean total DCS score decreased significantly from 40.2 to 31.7 after patients received information from the pharmacists (p < 0.001, paired t-test). Scores on all 5 subscales, namely, uncertainty, informed, values clarity, support, and effective decision, also significantly improved (p < 0.001 for all categories, paired t-test). CONCLUSIONS: The psychometric properties of the Japanese version of the DCS are considered appropriate for it to be administered to patients with cancer. Pharmacists' provision of information was able to decrease decisional conflict among patients with cancer who were recommended a new chemotherapy regimen.

Registry study of immune-related adverse events using electronic patient-reported outcome in patients with cancer receiving immune checkpoint inhibitors: protocol for a multicentre cohort study.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) is rapidly expanding in cancer treatment. ICIs have a unique safety profile, characterised by immune-related adverse events (irAEs). The safety profile of ICIs lacks patient experience and perspectives. This study primarily aims to obtain a database for descriptive research on the status of irAEs using the Patient-Reported Outcomes version of the Common Terminology Criteria (PRO-CTCAE) in patients with gastrointestinal cancer, lung cancer and malignant pleural mesothelioma treated with regimens containing ICIs. METHODS AND ANALYSIS: This is an ongoing, multicentre, observational study in Japan. Eligible patients must be at least 20 years old and have been diagnosed with lung cancer, malignant pleural mesothelioma or gastrointestinal cancer and plan to use ICIs. Participants will install the electronic PRO (ePRO) application and report adverse events via ePRO using PRO-CTCAE once weekly for up to 48 weeks. A registry will be established using background information obtained from medical records. The sample size is determined by 1 year projection without using statistical methods. Statistical analyses will include point estimates and 95% CIs for the incidence of each adverse event by cancer type and regimen at each time point. ETHICS AND DISSEMINATION: This research will be conducted per the Declaration of Helsinki, the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, and the revised Personal Information Protection Law. The study protocol was approved by the Ethics Committee (approval ID T2021-0180) of Tokyo Medical University Hospital on 15 October 2021. REGISTRATION DETAILS: The study began enrolling patients in December 2021. The target enrolment is 260; as of October 2022, 141 have been enrolled, and the enrolment is scheduled to end on 30 June 2023. TRIAL REGISTRATION NUMBER: UMIN000046418.

Psychological barriers to the use of opioid analgesics for treating pain in patients with advanced recurrent cancer (BAROC): protocol for a multicentre cohort study.

INTRODUCTION: Opioid analgesics are essential for treating cancer pain. However, patients are sometimes reluctant to use them because of concerns about addiction and dependence. Rapid pain relief following opioid administration may help overcome the psychological barriers to opioid analgesic use. This study aims to determine the relationship between psychological resistance to strong opioid analgesic use and pain amelioration speed in patients with advanced recurrent cancer. METHODS AND ANALYSIS: This ongoing, multicentre, observational study enrols patients aged 20 years or older with distant metastasis or advanced recurrent cancer receiving strong opioid analgesics for cancer pain for the first time. All participants, both inpatient and outpatient, were recruited from five Japanese hospitals. We are investigating the relationship between psychological barriers at the start of treatment and pain relief during the first week of treatment in these patients. The primary outcome is the Japanese version of the Barriers Questionnaire-II score at baseline. The secondary outcomes are the relationships between psychological barriers to strong opioid analgesic use and changes in pain over time. The participants are asked to fill out an electronic patient-reported outcome daily during the first week of treatment. The sample size was determined based on the number of patients in the year prior to study commencement who used strong opioid analgesics, met the eligibility criteria and could be expected to consent to participate in the study. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committee (approval ID B200600091) of Yokohama City University on 24 August 2020. The protocol has been reviewed by the institutional review boards at the four participating study sites. The results will be published in a peer-reviewed journal and will be presented at a relevant meeting. TRIAL REGISTRATION NUMBER: UMIN000042443.

Development of Japanese Versions of the Control Preferences Scale and Information Needs Questionnaire: Role of Decision-Making and Information Needs for Japanese Breast Cancer Patients.

PURPOSE: The importance of shared decision-making (SDM) between physicians and patients is increasingly recognized. In Japan, patients have shown more willingness to participate in treatment if medical professionals provide sufficient information; however, relationships between physicians and patients have traditionally been asymmetric, with patients accepting information from physicians without discussion. To explore the benefits of SDM in cancer treatment, including confidence in treatment decisions, satisfaction with treatment, and trust in healthcare providers, this study developed Japanese versions of the Control Preference Scale (CPS) and Information Needs Questionnaire (INQ). PATIENTS AND METHODS: Reliability and validity of the CPS and INQ were tested with 49 breast cancer patients. RESULTS: The CPS showed good test-retest reliability (kappa coefficient: 0.61, weighted kappa coefficient: 0.61, Kendall's tau coefficient: 0.61) and acceptable criterion validity. The INQ showed adequate consistency; the mean number of circular triads and coefficient of consistency were 3 (range 0-19) and 0.9 (range 0.37-1), respectively. Using the CPS and INQ to identify patients' roles in decision-making and information needs, results further suggested that breast cancer patients in Japan want to participate in SDM. Medical issues, including disease spread and cure, were found to be of high interest, while social and psychological issues, including sexual attractiveness, genetic risk, and family impact, tended to be low. CONCLUSION: The Japanese CPS and INQ can be used to assess patients' needs to improve care. Further, as patients' information needs change along the care trajectory, these tools should be used throughout treatment.

The Japanese version of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE): psychometric validation and discordance between clinician and patient assessments of adverse events.

BACKGROUND: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute as an adverse event assessment system to evaluate patients' symptoms, which tend to be underestimated in cancer clinical trials. The aim of this study was to assess the psychometric properties of the Japanese version of the PRO-CTCAE and the degree of adverse event assessment discordance between clinicians and patients. METHODS: A total of 187 cancer patients receiving systemic therapy were enrolled. Reproducibility, criterion validity, and responsiveness of the Japanese version of PROCTCAE were assessed. The EORTC QLQ-C30 was used as an external anchor. Discordance of assessment of adverse events between clinician and patients were also assessed using the CTCAE and PRO-CTCAE. RESULTS: A total of 187 participants (187 for criterion validity, 80 for reproducibility, and 100 for responsiveness), were analyzed (Mage = 62.4 years). All patients responded to at least one symptom item (M = 16). The mean (SD) intra-class correlation coefficients of overall reproducibility for the Japanese PRO-CTCAE was 0.63 (0.02). The correlation coefficient for the corresponding items in the EORTC QLQ-C30 and the Japanese PRO-CTCAE was high (Pearson r = 0.56-0.76). The analysis of responsiveness revealed significant dose-response trends (Jonckheere-Terpstra test, ps < 0.001). Depending on the adverse events, a discrepancy was observed in evaluation between the clinician and patient. CONCLUSIONS: These results revealed that there is underestimation in the assessment of adverse events in Japan, and that the Japanese version of the PRO-CTCAE had acceptable reliability and validity for common and clinically important symptoms.

Establishment of a novel lectin-antibody ELISA system to determine core-fucosylated haptoglobin.

BACKGROUND: Fucosylated haptoglobin (Fuc-Hpt) is a novel cancer biomarker that increases in various pathological conditions. We previously established a Fuc-Hpt lectin-antibody assay using Aleuria aurantia lectin (AAL), and applied this to diagnose several diseases, including various cancers. AAL recognizes both α1-3/1-4 and α1-6 fucosylation on N/O-linked glycans. These fucosylation types differ in biological function, and in regulation by different fucosyltransferases. Recently, we identified a novel lectin, Pholiota squarrosa lectin (PhoSL), which specifically recognizes α1-6 fucosylation (core-fucosylation). METHODS: We developed a lectin-antibody ELISA kit using PhoSL to determine core-Fuc-Hpt levels in sera from colorectal or pancreatic cancer patients. RESULTS: Serum levels of AAL-reactive Hpt are higher in pancreatic cancer patients, whereas those of PhoSL-reactive Hpt are higher in colorectal cancer patients. Mass spectrometry analyses of Hpt fucosylation levels were consistent with lectin-antibody ELISA results. Hpt-transfected colorectal cancer cell lines produced significant amounts of core-Fuc-Hpt, suggesting that colorectal cancer tissues produce core-Fuc-Hpt. CONCLUSIONS: These differences in Fuc-Hpt patterns might depend on cancer cells and the surrounding cells, which produce Hpt.

Assessment of Cancer-Related Fatigue, Pain, and Quality of Life in Cancer Patients at Palliative Care Team Referral: A Multicenter Observational Study (JORTC PAL-09).

INTRODUCTION: Cancer-related fatigue greatly influences quality of life in cancer patients; however, no specific treatments have been established for cancer-related fatigue, and at present, no medication has been approved in Japan. Systematic research using patient-reported outcome to examine symptoms, particularly fatigue, has not been conducted in palliative care settings in Japan. The objective was to evaluate fatigue, pain, and quality of life in cancer patients at the point of intervention by palliative care teams. MATERIALS AND METHODS: Patients who were referred to palliative care teams at three institutions and met the inclusion criteria were invited to complete the Brief Fatigue Inventory, Brief Pain Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative. RESULTS: Of 183 patients recruited, the majority (85.8%) were diagnosed with recurrence or metastasis. The largest group (42.6%) comprised lung cancer patients, of whom 67.2% had an Eastern Cooperative Oncology Group Performance Status of 0-1. The mean value for global health status/quality of life was 41.4, and the highest mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative symptom item score was for pain (51.0). The mean global fatigue score was 4.1, and 9.8%, 30.6%, 38.7%, and 20.8% of patients' fatigue severity was classified as none (score 0), mild (1-3), moderate (4-6), and severe (7-10), respectively. DISCUSSION: Cancer-related fatigue, considered to occur more frequently in cancer patients, was successfully assessed using patient-reported outcomes with the Brief Fatigue Inventory for the first time in Japan. Results suggested that fatigue is potentially as problematic as pain, which is the main reason for palliative care.

Twin studies on the effect of genetic factors on serum agalactosyl immunoglobulin G levels.

The level of immunoglobulin G (IgG) lacking the terminal galactose, referred to as agalactosyl IgG, was found to be increased in chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (IBD), particularly in Crohn's disease, which is suggested to have a genetic component. This oligosaccharide modification of IgG is mainly regulated by the expression of glyco-genes; however, the association between genetic factors and changes in the IgG glycosylation has not been fully elucidated. The aim of the present study was to assess the role of genetics in this process by comparing the serum agalactosyl IgG levels between members of monozygotic and dizygotic twin pairs who underwent medical check-ups at the same time. The serum agalactosyl IgG level was assayed using high-performance liquid chromatography. Hematological and biochemical markers, including γ-glutamyltranspeptidase (γGTP), alanine aminotransferase (ALT) and white blood cell (WBC) count, were also measured. Although the serum γGTP levels (and, to a lesser extent, ALT and WBC levels) exhibited a correlation within monozygotic twin pairs, agalactosyl IgG levels were not found to be correlated between members of either type of twin pairs. Thus, the role of genetic factors in determining serum agalactosyl IgG levels may be less significant compared to the effect of environmental factors or the onset of inflammatory disease.

Pancreatic fatty degeneration and fibrosis as predisposing factors for the development of pancreatic ductal adenocarcinoma.

OBJECTIVES: Knowledge of risk factors for development of pancreatic ductal adenocarcinoma (PDAC) is limited. To clarify the background condition of the pancreas for the development of PDAC, we analyzed pancreatic histological changes in noncancerous lesion specimens after pancreatectomy in PDAC patients. METHODS: Seventy-six patients with PDAC were enrolled in this study. The PDAC was in the pancreatic head in 37 patients, in the body in 31, and in the tail in 8. No patients had a history of clinical chronic pancreatitis. As controls, 98 patients without PDAC were enrolled. The following parameters were examined: fibrosis, fatty degeneration, and inflammatory cell infiltration. More than 5% of fatty degeneration in the specimen, more than 10% of fibrosis, and more than 5% of inflammatory cell infiltration were considered positive changes. RESULTS: Pancreatectomy specimens showed a higher ratio of positive change in fibrosis (86% vs 42%), fatty degeneration (72% vs 44%), and inflammatory cell infiltration (14% vs 3%) than control samples. Multivariate analyses demonstrated that each histological change was a significant, independent determinant for PDAC. CONCLUSIONS: Our study demonstrated that cryptogenic pancreatic inflammation with fatty changes represents an important predisposing factor for PDAC. Screening for subclinical chronic pancreatitis in healthy populations may enable the detection of PDAC at an early stage.