Citations

Normalization is the first critical step in microbiome sequencing data analysis used to account for variable library sizes. Current RNA-Seq based normalization methods that have been adapted for microbiome data fail to consider the unique characteristics of microbiome data, which contain a vast number of zeros due to the physical absence or under-sampling of the microbes. Normalization methods that specifically address the zero-inflation remain largely undeveloped. Here we propose geometric mean of pairwise ratios—a simple but effective normalization method—for zero-inflated sequencing data such as microbiome data. Simulation studies and real datasets analyses demonstrate that the proposed method is more robust than competing methods, leading to more powerful detection of differentially abundant taxa and higher reproducibility of the relative abundances of taxa.

The genomic DNA input for stool samples utilized for microbiome composition has not been determined. In this study, we determined the reliable threshold level under which conclusions drawn from the data may be compromised. We also determined the type of microbial bias introduced by less-than-ideal genomic input.

Normalization is the first critical step in microbiome sequencing data analysis used to account for variable library sizes. Current RNA-Seq based normalization methods that have been adapted for microbiome data fail to consider the unique characteristics of microbiome data, which contain a vast number of zeros due to the physical absence or under-sampling of the microbes. Normalization methods that specifically address the zero inflation remain largely undeveloped. Here we propose GMPR - a simple but effective normalization method - for zero-inflated sequencing data such as microbiome data. Simulation studies and real datasets analyses demonstrate that the proposed method is more robust than competing methods, leading to more powerful detection of differentially abundant taxa and higher reproducibility of the relative abundances of taxa.

SummaryThe landscape of oncology drug development has recently changed with the emergence of molecularly targeted agents and immunotherapies. These new therapeutic agents appear more likely to induce multiple low or moderate grade toxicities rather than dose limiting toxicities. Various model-based dose finding designs and toxicity severity scoring systems have been proposed to account for toxicity grades, but they are difficult to implement because of the use of complicated dose–toxicity models and the requirement to refit the model at each decision of dose escalation and de-escalation. We propose a generalized Bayesian optimal interval design, gBOIN, that accommodates various existing toxicity grade scoring systems under a unified framework. As a model-assisted design, gBOIN derives its optimal decision rule on the basis of the exponential family of distributions but is carried out in a simple way as the algorithm-based design: its decision of dose escalation and de-escalation involves only a simple comparison of the sample mean of the end point with two prespecified dose escalation and de-escalation boundaries. No model fitting is needed. We show that gBOIN has the desirable finite property of coherence and a large sample property of consistency. Numerical studies show that gBOIN yields good performance that is comparable with or superior to that of some existing, more complicated model-based designs. A Web application for implementing gBOIN is freely available from http://www.trialdesign.org.

Abstract BACKGROUND: Arm morbidity, the most reported comorbidity following axillary surgery for breast cancer, is of particular importance in young patients given the longer survivorship period and detrimental effects of arm-morbidity on body image and social-, home- and personal care functions. We assessed the incidence of arm-morbidity stratified by local therapy strategies in young women enrolled in the Young Women's Breast Cancer Study (YWS). PATIENTS AND METHODS: The YWS, a multicenter prospective cohort study, established to explore biological, medical and psychosocial issues in young breast cancer patients, enrolled 1302 women with stage 0-4 breast cancer ≤40 years of age from October 2006 to June 2016. For this analysis, we examined incidence of patient reported arm-swelling or decreased range of motion (ROM) 1-year after diagnosis using relevant items of the CARES-SF. Patients with stage 4 disease (n = 60), those for whom no information on arm-morbidity was available (n=198) and those with bilateral cancer with different local therapy strategies on each side (n=7), were excluded. We performed logistic regression analyses to identify risk factors for arm morbidity. RESULTS: Among 1037 patients (median age 37 years), 13% and 40% reported arm-swelling or decreased ROM, respectively, in the ipsilateral arm at 1-year. 52% (n=539) of patients underwent SLNB and 39% (n=407) ALND. The incidence of arm-swelling was 4% (11/280) in patients who underwent SLNB without RT, 8% (21/252) in patients who underwent SLNB with RT, 20% (13/66) in patients who underwent ALND without RT and 24% (84/337) in patients who received ALND with RT. The incidence of decreased ROM was 21% (59) in patients who underwent SLNB without RT, 34% (86) in patients who underwent SLNB with RT, 33% (22) in patients who underwent ALND without RT and 44% (148) in patients who received ALND with RT. Being overweight, uncomfortable financial status, T4 tumors, ALND and RT were independently associated with an increased risk of arm-swelling. Overweight, mastectomy and RT were independently associated with an increased risk of a decreased ROM Table 1). Results of the logistic regression analyses. Arm swelling at 1 year (n=137)Decreased ROM at 1 year (n=335) ORpORpBMI <18.50.70.620.70.4018.5-24.9ref ref 25-29.91.70.031.50.05≥301.10.791.10.70Financial comfort Comfortableref ref Uncomfortable0.60.020.90.67pT stage pT1ref ref pT21.20.621.50.13pT31.20.701.30.63pT44.40.032.20.29pN stage pN0ref ref pN11.10.851.70.08pN23.00.111.90.27pN33.20.112.70.16Surgery BCSref ref Mastectomy1.20.611.80.02Bilateral mastectomy1.10.841.60.06Axillary surgery SLNBref ref SLNB + ALND3<0.011.30.33ALND3.6<0.011.00.90RT Noref ref Yes1.80.052.4<0.01Note. In these analysis we also corrected for age, incidence year, employment status, stage of disease, reconstructive surgery, and chemotherapy treatment. . CONCLUSION: Patient reported outcomes reveal high rates of arm-swelling and decreased ROM 1 year after breast cancer diagnosis in a large prospective cohort of young breast cancer survivors. These findings suggest an opportunity for pre-operative education and early intervention for arm impairment in this population. Citation Format: Kuijer A, Dominici LS, Rosenberg SM, Hu J, Gelber S, Di Lascio S, Ruddy KJ, Wong J, Tamimi RM, Schapira L, Borges VF, Come SE, Sprunck-Harrild K, Partridge AH, King TA. Risk of arm morbidity after local therapy in young breast cancer survivors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-03.

Abstract Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid–binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII−Ly6C− phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM. Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343–55. ©2018 AACR.

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre‐existing nevus, causing over‐interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark’s) level of IV‐V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that “inverted type‐A nevus” might be considered a variant of the two.