A Bayesian feature allocation model for identifying cell subpopulations using CyTOF data.

A Bayesian feature allocation model (FAM) is presented for identifying cell subpopulations based on multiple samples of cell surface or intracellular marker expression level data obtained by cytometry by time of flight (CyTOF). Cell subpopulations are characterized by differences in marker expression patterns, and cells are clustered into subpopulations based on their observed expression levels. A model-based method is used to construct cell clusters within each sample by modeling subpopulations as latent features, using a finite Indian buffet process. Non-ignorable missing data due to technical artifacts in mass cytometry instruments are accounted for by defining a static missingship mechanism. In contrast with conventional cell clustering methods, which cluster observed marker expression levels separately for each sample, the FAM-based method can be applied simultaneously to multiple samples, and also identify important cell subpopulations likely to be otherwise missed. The proposed FAM-based method is applied to jointly analyse three CyTOF datasets to study natural killer (NK) cells. Because the subpopulations identified by the FAM may define novel NK cell subsets, this statistical analysis may provide useful information about the biology of NK cells and their potential role in cancer immunotherapy which may lead, in turn, to development of improved NK cell therapies.

A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada.

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19-99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

Effect of proximity to specialty care on outcomes for biliary cancers: a population-based retrospective cohort study.

BACKGROUND: The management of biliary cancers is complex and requires a multidisciplinary approach. Because it is unknown how access to specialty care affects resource use and survival in patients with biliary cancer, we conducted a population-based study to understand the needs of these patients and the relation of geography to care delivery and clinical outcomes for biliary cancer in Alberta. METHODS: All patients with biliary cancer diagnosed in Alberta from Sept. 1, 2001, to Dec. 31, 2015 were included in this population-based retrospective cohort study. Data were extracted from administrative databases and the 2011 Canadian census. Driving time and types of medical services were tracked throughout the patients' clinical course. We categorized proximity to specialty care according to driving time to the nearest specialist. The primary outcome was overall survival. We conducted Cox proportional hazard regression to evaluate the effects of driving time on overall survival and multivariate logistic regression to evaluate the effect of driving time on treatment types and stage at diagnosis. RESULTS: We identified 1610 patients with biliary cancer; they accounted for 117 381 medical encounters. Patients living 120 minutes or more from the nearest hepatobiliary surgeon and from the nearest cancer centre had significantly decreased survival (hazard ratio [and 95% confidence interval (CI)] 1.27 [1.17-1.37]) and 1.27 [1.14-1.41], respectively). Location of residence was not associated with advanced stage or probability of undergoing surgery or a biliary drainage procedure. Patients who lived 120 minutes or more from a cancer centre were less likely than those who lived less than 120 minutes away to receive chemotherapy (odds ratio 0.51, 95% CI 0.29-0.88). Subgroup analysis showed that the effect of travel time was especially pronounced among those who received only best supportive care and those who had biliary drains. INTERPRETATION: Geography and accessibility to specialty care affected survival in patients with biliary cancer. Further study is required to understand how patients with biliary drains and those receiving best supportive care are affected by proximity to specialty care. This will aid in the identification of strategies to provide improved care for this subgroup who are particularly affected by geography.

Predictive and Prognostic Properties of Human Equilibrative Nucleoside Transporter 1 Expression in Gemcitabine-Treated Pancreatobiliary Cancer: A Meta-Analysis.

PURPOSE: Gemcitabine, the primary drug for the treatment of pancreatobiliary cancer (PBC), requires human equilibrative nucleoside transporter 1 (hENT1) to enter cells. High tumoral hENT1 expression has been linked with improved survival among patients with PBC treated with gemcitabine; however, this finding has been inconsistent, and studies used different expression assays. METHODS: Databases were reviewed for studies that examined hENT1 and clinical outcome in PBC. Of 307 publications, 34 studies were found that used immunohistochemistry (IHC) with one of eight anti-hENT1 antibody assays. Five studies were excluded for redundancy, and 29 studies underwent detailed review. RESULTS: On average, 51% of tumor samples had high hENT1 expression (range, 7% to 92%). Among studies that examined hENT1 expression and overall survival (OS), 58% (15 of 26 studies) showed an association between high tumoral hENT1 and improved OS for gemcitabine-treated patients. Among 10D7G2 antibody studies, 88% (seven of eight studies) demonstrated this association. Studies with other antibodies-in particular, SP120 (two of nine studies)-were less consistent. The ability to detect an association between improved OS and high hENT1 was antibody dependent (χ2 P = .0237). An association between high tumoral hENT1 expression and improved disease-free/progression-free survival (DFS/PFS) was demonstrated in 71% of studies (15 of 21 studies). Pooled hazard ratio (HR) analyses of all antibody studies demonstrated a link between high hENT1 tumor expression and improved OS (HR, 0.674; 95% CI, 0.509 to 0.893; P = .006) and DFS/PFS (HR, 0.740; 95% CI, 0.517 to 0.1.059; P = .10). This signal was stronger among studies that used the 10D7G2 antibody in comparison to those in which another antibody was used, with HRs of 0.488 (95% CI, 0.396 to 0.602; P < .001) and 0.410 (95% CI, 0.280 to 0.599; P < .001), respectively. CONCLUSION: High tumoral hENT1 expression on IHC with 10D7G2 is a strong and reproducible prognostic marker for improved outcome among gemcitabine-treated patients with PBC.

A multicentre, open-label phase II study of Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

Sexual Dysfunction among Filipino breast cancer patients

INTRODUCTION: Sexual function is an important aspect of quality of life, and can be drastically affected in ill patients. Very few studies (and apparently none among Filipinas) looked into sexual dysfunction among females with breast cancer (BrCa); prevalence also is not well defined. This study evaluates the prevalence of sexual dysfunction among Filipino patients with BrCa, and assesses which treatment or if duration of illness, age, BMI, smoking history, diabetes, hypertension significantly contributed to the dysfunction.METHODS: A cross sectional study was conducted among BrCa patients consulting at the outpatient medical oncology clinic of a government tertiary hospital. Study population included those diagnosed and was with breast cancer over a 3-months period, with a calculated sample size of 60 (within 81±10% prevalence rate, Cl 95%). A validated translated version of the Female Sexual Function Index (FSFI) 19-item questionnaire that looked into 6 domains (arousal, lubrication, desire, pain, orgasm, and satisfaction) was used. Sexual dysfunction was defined as an FSFI score of RESULTS: Of the 97 respondents, mean age was 49.4 years old and mean BMI of 24.8. About 78% received chemotherapy, 26% hormonal therapy. 15% radiotherapy, 82% modified radical mastectomy (MRM), and 71% received both MRM and chemotherapy at the time of interview. Duration of cancer wasmonths in 72% of subjects. There were 97.9% who had sexual dysfunction which is similar to prevalence rates (64-98%) in other studies. Age, BMI, smoking history, hypertension, diabetes mellitus, chemotherapy, surgery, hormonal therapy, radiation therapy, and duration of illness were shown not to be significant predictors of sexual dysfunction among Filipinas with BrCa by bivariate analysis.CONCLUSION: Sexual dysfunction is highly prevalent among female Filipino BrCa patients. Knowing such high prevalence should prompt health care providers to include interventions to improve quality of life of BrCa patients, including their sexual life.

Chemotherapy-induced neutropenia, anemia and thrombocytopenia among Filipino breast cancer patients on adjuvant hemotherapy

INTRODUCTION: Cytotoxic chemotherapy places all cancer patients at risk of developing myelosuppression. Different chemotherapy regimens could lead to development of neutropenia, anemia and thrombocytopenia which may lead to delays in facilitating chemotherapy and also may place cancer patients at risk of developing severe complications which may be life threatening. This study determined the incidence of neutropenia, anemia, and thrombocytopenia per cycle of chemotherapy starting after the 1st cycle among non-metastatic breast cancer patients. It also evaluated if age, size of primary tumor, number of positive lymph nodes, IHC result, BMI, co-morbidities and chemotherapy used were associated with the development of neutropenia, anemia and thrombocytopenia during the 10 cycle of chemotherapy; this may help in ascertaining which patients may need more intensive monitoring during subsequent chemotherapy sessions.METHODS: This is a time series study wherein the CBC results starting prior 1° chemotherapy cycle were gathered from medical charts of non-metastatic breast cancer patients receiving cyclophosphamide/ doxorubicin/ docetaxel/ fluororuracil chemotherapy at UP-PGH and JRRMMC Medical Oncology Clinics enrolled under the DOH-NCPAM BCMAP program, from 1 January 2009 to 31 June 2014. Incidence rates of neutropenia, anemia and thrombocytopenia were recorded per cycle of chemotherapy. Severity of myelosuppression was graded based on the Common Toxicity Criteria of the National Cancer Institute Version 2.0. Possible predictors of myelosuppression were assessed focusing on the 1st cycle of chemotherapy where interventions were not yet done. Standard statistical methods were used for the descriptive analysis. Variables were analyzed using the Chi square test and logistic regression; level of significance was at pAfter the 1st chemotherapy cycle, the incidence of neutropenia was 4.67% (35 patients), anemia 2.27% (17 patients), and thrombocytopenia 0.8% (6 patients). Of these patients, only 1.17% (9 patients) experienced severe neutropenia and 0.27% (2 patients) experienced grade 3-4 anemia. No patient experienced grade 3-4 thrombocytopenia.Age, size of primary tumor, number of positive lymph nodes, IHC result, BMI, co-morbidities and chemotherapy used were not associated with risk for myelosuppression during the 1st cycle of chemotherappy.CONCLUSION: Incidence rates of neutropenia, anemia and thrombocytopenia were minimal in non-metastatic breast cancer patients undergoing cytotoxic chemotherapy, with low rates of severe myelosupression. Myelosupression from standard doxorubicin/ cyclophosphamide/ docetaxel/ fluoracil containing chemotherapy regimens can be given to non-metastatic breast cancer patients, completing required number of chemotherapy cycles with nil interruption or delay.

Immunohistochemical profile, pattern of recurrence, and time to progression of non-metastatic breast cancer patients of the Department of Health-Breast Cancer Medicines Access Program

BACKGROUND: Breast cancer remains to be the leading cause of malignancy among women and survival rates vary worldwide. Molecular and immunohistochemical (NC) profiling of breast cancer has emerged to improve treatment, which led to 6 different breast cancer subtypes luminal-A, luminal-B, Her-2 enriched, basal-like, daudin low, and normal breast. Essentially, this guides clinicians as to the choice of treatment and prognostication of disease. This study evaluates the characteristics of the different IHC subtypes of breast cancer among Filipinos as to pattern of recurrence and time to progression (TIP) within their 1st 2 years of follow-up.METHODS: This is a retrospective cohort study, approved by the University of the Philippines Manila Research Ethics Board (UPMREB). Study population included breast cancer patients enrolled in the DOH-BCMAP and managed at the medical oncology clinics of the Philippine General Hospital (PGH) and Jose R. Reyes Memorial Medical Center (JRRMMC) from 1 May 2011 to 31 December 2013. Patients' demographics, disease and treatment profile were gathered from the medical charts. Patients were grouped into 12 different IHC subtypes utilizing only IHC staining results of Her2neu, ER and PR. Disease progression/ relapse and time to progression (UP) were primary outcomes analyzed and compared between subtypes using SPSS.RESULTS: There were 368 eligible patients; 50% were >50 years old, 48% postmenopausal, 34% stage IIA, and 94% had invasive ductal carcinoma. About 88% completed their chemotherapy regimen, mostly AC-T. At 1 to 2 years follow-up, 18% had disease progression, mostly distant metastasis, with HER2neu(-)/ER(-)/PR(-), HER2(+), and HER2neu(-)/ER(+)/PR(+) subtypes having the most number of disease progression. The HER2neu(-)/ER(-)/PR(-) subtype had the shortest median TTP (11 months 9sd). HER2(+) subtype had median TTP of 14±8 sd, while HER2neu(-)/ER(+)/PR(+) had median TTP at 11.6±7.41 sd. The median TTPs among the different IHC subtypes were statistically comparable. CONCLUSION: Filipinas with non-metastatic breast cancer after surgery and mainly on adjuvant chemotherapy started to develop disease progression/ relapse within the first 2 years of follow-up; 82% had no relapse. At these early years of follow-up, the median TTPs among the different breast cancer IHC subtypes who went into relapse were comparable, although HER2neu(+) regardless of ER/PR subtype tended to have more disease progression, followed by HER2neu(-)/ ER(-)/ regardless of PR subtype, and then HER2neu(-)/ ER(+)/ regardless of PR subtype. IHC resultant HER2neu(+) regardless of ER/PR and HER2neu(-)/ER(-)/PR(-/+) subtypes can serve as early prognosticators of breast cancer relapse.