Characterization of circulating immune cells in acute Kawasaki disease suggests exposure to different antigens.

Kawasaki disease (KD) is an acute pediatric vasculitis of unknown etiology that can cause coronary artery aneurysms, and is the leading cause of acquired heart disease in children. We studied aspects of the innate and adaptive immune response in 17 acute KD children prior to treatment with intravenous immunoglobulin. Distinct patterns within the innate immune response correlated with specific clinical features. Proinflammatory myeloid dendritic cells (mDC) were abundant in four of 17 (23·5%) subjects who were older and manifested severe inflammation with clinical myocarditis and elevated hepatobiliary enzyme levels. Of the nine subjects with low levels of anti-inflammatory, tolerogenic mDC, six had enlarged cervical lymph nodes at diagnosis. In contrast, the adaptive immune repertoire varied greatly with no discernible patterns or associations with clinical features. Two subjects with aneurysms had numerous circulating CD8+ T cells. Ten subjects showed low CD4+ T cell numbers and seven subjects had CD4+ T cells in the normal range. CD4+ T cells expressed interleukin-7 receptor (IL-7R), suggesting repeated antigenic stimulation. Thymic-derived regulatory T cells (nTreg ) and peripherally induced regulatory T cells (iTreg ) were also enumerated, with the majority having the nTreg phenotype. Natural killer (NK) and NK T cell numbers were similar across all subjects. Taken together, the results of the immune monitoring suggest that KD may have multiple triggers that stimulate different arms of the innate and adaptive compartment in KD patients. Thus, it is possible that diverse antigens may participate in the pathogenesis of KD.

Current status of integrating oncology and palliative care in Japan: a nationwide survey.

BACKGROUND: Palliative care (PC) is increasingly recognized as essential for oncology care, and several academic societies strongly recommend integrating oncology and palliative care (IOP) in daily practice. Similarly, the Japanese government encouraged the implementation of IOP through the Cancer Control Act of 2007; however, its detailed progress remains unclear. Therefore, this cross-sectional nationwide survey was conducted to investigate the current status and hospital executive physicians' perception of IOP. METHODS: The questionnaire was developed based on IOP indicators with international consensus. It was distributed to executive physicians at all government-designated cancer hospitals (DCHs, n = 399) and matched non-DCHs (n = 478) in November 2017 and the results were compared. RESULTS: In total, 269 (67.4%) DCHs and 259 (54.2%) non-DCHs responded. The number of PC resources in DCHs was significantly higher than those in non-DCHs (e.g., full-time PC physicians and nurses, 52.8% vs. 14.0%, p < 0.001; availability of outpatient PC service ≥3 days per week, 47.6% vs. 20.7%, p < 0.001). Routine symptom screening was more frequently performed in DCHs than in non-DCHs (65.1% vs. 34.7%, p < 0.001). Automatic trigger for PC referral availability was limited (e.g., referral using time trigger, 14.9% vs. 15.3%, p = 0.700). Education and research opportunities were seriously limited in both types of hospitals. Most executive physicians regarded IOP as beneficial for their patients (95.9% vs. 94.7%, p = 0.163) and were willing to facilitate an early referral to PC services (54.7% vs. 60.0%, p < 0.569); however, the majority faced challenges to increase the number of full-time PC staff, and < 30% were planning to increase the staff members. CONCLUSIONS: This survey highlighted a considerable number of IOP indicators met, particularly in DCHs probably due to the government policy. Further efforts are needed to address the serious research/educational gaps.

Dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube, or primary peritoneal carcinomas.

PURPOSE: Weekly dose-dense paclitaxel with carboplatin every 3 weeks (dose-dense TC) provides good efficacy, and neoadjuvant chemotherapy is common for advanced-stage disease. However, it is unclear the efficacy and safety of dose-dense TC as neoadjuvant chemotherapy. Therefore, we evaluated neoadjuvant dose-dense TC chemotherapy for advanced-stage ovarian carcinoma. METHODS: We retrospectively reviewed cases of ovarian carcinoma that were not suited for primary debulking surgery (2003-2014). The patients received neoadjuvant dose-dense TC chemotherapy, followed by interval debulking surgery and adjuvant chemotherapy. RESULTS: We identified 74 patients (mean age 60 years, range 39-85 years). The FIGO stages were IIIC (39/74, 52.7%) and IV (34/74, 45.9%). Fifty-six patients (75.6%) had a performance status of 0-1. The adverse events were grade 3/4 neutropenia (55.4%), anemia (44.6%), thrombocytopenia (21.6%), and peripheral neuropathy (8.1%); no treatment-related deaths were observed. Among the 66 patients who underwent debulking (89.2%), 55 patients (74.3%) achieved optimal debulking and 47 patients (63.5%) achieved complete resection. The median progression-free and overall survivals were 19.0 months (95% CI 16.2-23.7 months) and 55.1 months (95% CI 44.6 months to not estimable), respectively. A performance status of 2-3 was independently associated with poor prognosis (hazard ratio 3.84; p = 0.001). CONCLUSIONS: Neoadjuvant dose-dense TC chemotherapy was effective (complete resection in >60% of cases) and tolerable for advanced-stage ovarian carcinoma.

Clinical and microarray analysis of breast cancers of all subtypes from two prospective preoperative chemotherapy studies.

BACKGROUND: We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts. METHODS: Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA-IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0. RESULTS: Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR-/HER2- cancers. Age, pathologic complete response, HR-/HER2- status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004). CONCLUSIONS: This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention.

Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently, there is no biomarker for targeted therapy. PATIENTS AND METHODS: Tissue samples were obtained from 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. We examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of patients. RESULTS: In the tumor tissues, phospho-AKT (pAKT) expression was significantly related to HER4 expression. Expression of each of these biomarkers was significantly related to longer EFS (P = 0.024 and 0.03, respectively). pERK expression was also a good prognostic factor regarding EFS and OS in TNBC (P = 0.002 and 0.006, respectively). We also identified a correlation between epidermal growth factor receptor positivity and insulin-like growth factor receptor type 1 positivity (P = 0.001). pERK and T-stage (1-3 versus >3) were independent good prognostic factors by multivariate analysis. CONCLUSIONS: We determined that tumors expressing pAKT or pERK are a good prognostic subtype in node-positive TNBC. Different targeted therapies may be necessary for TNBC that involves activation of PI3K/AKT or MAPK pathways.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Can oncologists predict survival for patients with progressive disease after standard chemotherapies?

BACKGROUND: Prediction of prognosis is important for patients so that they can make the most of the rest of their lives. Oncologists could predict survival, but the accuracy of such predictions is unclear. METHODS: In this observational prospective cohort study, 14 oncologists treating 9 major adult solid malignancies were asked to complete questionnaires predicting survival based on performance status, oral intake, and other clinical factors when patients experienced progressive disease after standard chemotherapies. Clinically predicted survival (cps) was calculated by the oncologists from the date of progressive disease to the predicted date of death. Actual survival (as) was compared with cps using Kaplan-Meier survival curves, and factors affecting inaccurate prediction were determined by logistic regression analysis. The prediction of survival time was considered accurate when the cps/as ratio was between 0.67 and 1.33. RESULTS: The study cohort consisted of 75 patients. Median cps was 120 days (interquartile range: 60-180 days), and median as was 121 days (interquartile range: 40-234 days). The participating oncologists accurately predicted as within a 33% range 36% of the time; the survival time was overestimated 36% of time and underestimated 28% of the time. The factors affecting the accuracy of the survival estimate were the experience of the oncologist, patient age, and information given about the palliative care unit. CONCLUSIONS: Prediction of cps was accurate for just slightly more than one third of all patients in this study. Additional investigation of putative prognostic factors with a larger sample size is warranted.

Pregnancy in women with a history of Kawasaki disease: management and outcomes.

OBJECTIVE: To characterise the obstetrical management and outcomes in a series of women with a history of Kawasaki disease (KD) in childhood. DESIGN: Retrospective case series. SETTING: Tertiary healthcare setting in the USA. POPULATION: Women with a history of KD in childhood. METHODS: Women completed a detailed health questionnaire and participated in research imaging studies as part of the San Diego Adult KD Collaborative Study. MAIN OUTCOME MEASURES: Obstetrical management, complications during pregnancy and delivery, and infant outcomes. RESULTS: Ten women with a history of KD in childhood carried a total of 21 pregnancies to term. There were no cardiovascular complications during labour and delivery despite important cardiovascular abnormalities in four of the ten subjects. Pregnancy was complicated by pre-eclampsia and the post-partum course was complicated by haemorrhage in one subject each. Two of the 21 progeny subsequently developed KD. CONCLUSIONS: Women with important cardiovascular sequelae from KD in childhood should be managed by a team that includes both a maternal-fetal medicine specialist and a cardiologist. Pre-pregnancy counselling should include delineation of the woman's current functional and structural cardiovascular status and appropriate adjustment of medications, but excellent outcomes are possible with appropriate care. Review of the English and Japanese literature on KD and pregnancy revealed the occurrence of myocardial infarction during pregnancy in women with missed KD and aneurysms that were not diagnosed until their acute event. Our study highlights the need for counselling with regard to the increased genetic risk of KD in offspring born to these mothers.

Immune-monitoring in Kawasaki disease patients treated with infliximab and intravenous immunoglobulin.

The expansion of regulatory T cells (Treg ) controls inflammation in children with acute Kawasaki disease (KD). Blockade of tumour necrosis factor (TNF)-α is an emerging therapy for KD patients with refractory inflammation, but there is concern that this therapy could impede the host immune regulation. To define the effect of TNF-α blockade, we conducted ex-vivo immune-monitoring in KD subjects who participated in a randomized, double-blind, placebo-controlled clinical trial of the addition of infliximab to standard intravenous immunoglobulin (IVIG) therapy. We enumerated circulating myeloid and plasmocytoid dendritic cells (DC), regulatory T cells (Treg ) and memory T cells (Tmem ) in 14 consecutive, unselected KD patients (seven treated with IVIG, seven with IVIG + infliximab) at three time-points: (i) acute phase prior to treatment, (ii) subacute phase and (iii) convalescent phase. Myeloid DC (mDC), but not plasmacytoid DC (pDC), were numerous in the peripheral blood in acute KD subjects and decreased in the subacute phase in both IVIG(-) and IVIG (+) infliximab-treated groups. The co-stimulatory molecule for antigen presentation to T cells and CD86 decreased in mDC from acute to subacute time-points in both treatment groups, but not in the single patient who developed coronary artery aneurysms. We also defined tolerogenic mDC that expand in the subacute phase of KD not impaired by infliximab treatment. Treg and Tmem expanded after treatment with no significant differences between the two groups. Treatment of KD patients with infliximab does not adversely affect generation of tolerogenic mDC or the development of T cell regulation and memory.

The basis examination of leukocyte-platelet aggregates with CD45 gating as a novel platelet activation marker.

INTRODUCTION: Platelet activation in circulation is considered to be associated with thrombosis and inflammation; thus, sensitive and easy-to-use markers are necessary. In this study, we established a simple and rapid protocol to clinically examine leukocyte-platelet aggregate formation associated with activated platelets in circulation. METHODS: Whole blood was stained with PC5-conjugated anti-CD45 monoclonal antibody and fluorescent isothiocyanate-conjugated anti-CD41 monoclonal antibody for leukocyte-platelet aggregate analysis. For platelet activation, 5 µm thrombin receptor-activated peptide (TRAP) or 2 µg/mL collagen was added. Samples were analyzed by EPICS XL (Beckman Coulter, Miami, FL, USA). Monocytes, neutrophils, and lymphocytes were gated based on differences in CD45 fluorescence intensity and side scatter. For each gate, the percentage (%) of platelets expressing CD41 was analyzed. Same drawing sample was stained with anti-CD62P monoclonal antibody. Platelet CD62P expression was then analyzed with gating for platelet cell population. RESULTS: We analyzed leukocyte-platelet aggregates and platelet CD62P expression in 18 healthy individuals. Leukocyte-platelet aggregates, mainly monocyte-platelet aggregates, increased when platelets were activated by platelet agonists. Monocyte-platelet aggregates and neutrophil-platelet aggregates also increased over time with mild platelet activation. CONCLUSION: Leukocyte-platelet aggregates, mainly monocyte-platelet aggregates, appear to be a sensitive marker of platelet activation in circulation.

Efficacy of pleurodesis for malignant pleural effusions in breast cancer patients.

This study retrospectively compared long-term outcomes between two groups of breast cancer patients with malignant pleural effusion (MPE): those receiving only systemic therapy (ST) and those receiving ST following initial pleurodesis (P-ST). We identified 180 breast cancer patients from the National Cancer Center Hospital (Tokyo, Japan) database who had received ST and P-ST as an initial treatment for MPE between 1997 and 2008 for study inclusion. Pleural progression-free survival (PPFS) was defined as the time from ST in the ST group and from pleurodesis in the P-ST group to the first observation of pleural progression or death from any cause. Of the 180 patients, 78 received ST and 102 received P-ST after MPE diagnosis. Median duration of follow-up was 12.7 months (range 0.9-80.1 months). Median PPFS for the ST group and the P-ST group was 4.1 and 8.5 months, respectively. The difference in PPFS between the two groups was statistically significant (p < 0.001) and the hazard ratio after adjusting for prognostic factors in the P-ST group relative to the ST group was 0.24. Our results suggest that the efficacy of P-ST may be superior to that of ST alone with respect to local control of pleural effusions in breast cancer patients.

The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma.

BACKGROUND: To elucidate the incidence and mechanisms of sunitinib-induced thyroid atrophy, we investigated serial volumetric and functional changes, and evaluated histological changes of the thyroid gland in metastatic renal cell carcinoma patients who received sunitinib. METHODS: Thyroid volume (by computed tomography volumetry) and thyroid function were measured at baseline, during the treatment, and at post-treatment periods. Histological evaluation of the thyroid gland was performed in four autopsied patients. RESULTS: The median reduction rate in thyroid volume at last evaluation during sunitinib treatment was 30% in all 17 patients. The incidence of hypothyroidism during sunitinib treatment was significantly higher in the high reduction rate group (n=8; more than 50% reduction in volume) than in the low reduction rate group (n=9; less than 50% reduction in volume). Half of the patients in the high reduction rate group exhibited a transient thyroid-stimulating hormone suppression, suggesting thyrotoxicosis during sunitinib treatment. Histological evaluation demonstrated atrophy of thyroid follicles and degeneration of follicular epithelial cells without critical diminution of vascular volume in the thyroid gland. CONCLUSION: Thyroid atrophy is frequently observed following sunitinib treatment and may be brought about by sunitinib-induced thyrotoxicosis or the direct effects of sunitinib that lead to degeneration of thyroid follicular cells.

Compliance with Good Clinical Practice in oncology registration trials in Japan.

BACKGROUND: This study aimed to examine the quality in oncology registration trials for new drug application (NDA) or supplemental new drug application (sNDA) as extensions of the indications for use in Japan based on Good Clinical Practice (GCP) audit findings. MATERIALS AND METHODS: We collected audit reports of on-site GCP inspections for registration trials in 383 NDAs or sNDAs that were reviewed by the Pharmaceuticals and Medical Devices Agency between the fiscal years 2004 and 2009. RESULTS: Among the 40 audits for oncology drug applications, the frequencies at which one or more deficiencies ascribed to institution, investigator, sponsor, and institutional review board were found to be 15 (37.5%), 13 (32.5%), 21 (52.5%), and 10 (25.0%), respectively. The exclusion of patients from the review objective due to serious violations of GCP in 40 audits for oncology drug applications was observed in 2 (5.0%) cases, whereas that in the remaining 343 audits for other drug applications was observed in 40 (11.7%) cases. CONCLUSION: The overall compliance of GCP in oncology registration trials was moderately better than that in registration trials for other diseases, although there was no statistically significant difference between them.

FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer.

BACKGROUND: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab. PATIENTS AND METHODS: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed. RESULTS: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034). CONCLUSION: The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer.

Predictors of recurrence in breast cancer patients with a pathologic complete response after neoadjuvant chemotherapy.

BACKGROUND: Although a pathologic complete response (pCR) after neoadjuvant chemotherapy is associated with favourable outcomes, a small proportion of patients with pCR have recurrence. This study was designed to identify factors predictive of recurrence in patients with pCR. METHODS: A total of 449 breast cancer patients received neoadjuvant chemotherapy, and 88 evaluable patients had a pCR, defined as no evidence of invasive carcinoma in the breast at surgery. The clinical stage was II in 61 patients (69%), III in 27 (31%). All patients received taxanes and 92% received anthracyclines. Among 43 patients with HER2-positive tumours, 27 received trastuzumab. Cox regression analyses were performed to identify predictors of recurrence. RESULTS: Median follow-up was 46.0 months. There were 12 recurrences, including 8 distant metastases. The rate of locoregional recurrence was 10.4% after breast-conserving surgery, as compared with 2.5% after mastectomy. Multivariate analysis revealed that axillary metastases (hazard ratio (HR), 13.6; P<0.0001) and HER2-positive disease (HR, 5.0; P<0.019) were significant predictors of recurrence. Five of six patients with both factors had recurrence. Inclusion of trastuzumab was not an independent predictor among patients with HER2-positive breast cancer. CONCLUSION: Our study results suggest that HER2 status and axillary metastases are independent predictors of recurrence in patients with pCR.