The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the mainstay treatment for locally advanced rectal cancer. Variable degrees of tumor regression are observed after nCRT and alternative treatment strategies, including close surveillance without immediate surgery, have been investigated to spare patients with complete tumor regression from potentially adverse outcomes of radical surgery. However, clinical and radiological assessment of response does not allow accurate identification of patients with complete response. In addition, surveillance for recurrence is similarly important for these patients, as early detection of recurrence allows salvage resections and adjuvant interventions. We report the use of liquid biopsies and personalized biomarkers for monitoring treatment response to nCRT and detecting residual disease and recurrence in patients with rectal cancer. We sequenced the whole-genome of four rectal tumors to identify patient-specific chromosomal rearrangements that were used to monitor circulating tumor DNA (ctDNA) in liquid biopsies collected at diagnosis and during nCRT and follow-up. We compared ctDNA levels to clinical, radiological and pathological response to nCRT. Our results indicate that personalized biomarkers and liquid biopsies may not be sensitive for the detection of microscopic residual disease. However, it can be efficiently used to monitor treatment response to nCRT and detect disease recurrence, preceding increases in CEA levels and radiological diagnosis. Similar good results were observed when assessing tumor response to systemic therapy and disease progression. Our study supports the use of personalized biomarkers and liquid biopsies to tailor the management of rectal cancer patients, however, replication in a larger cohort is necessary to introduce this strategy into clinical practice.     

Pictorial essay of ultrasound‐reconstructed coronal plane images of the uterus in different uterine pathologies

Imaging in the major planes (horizontal, coronal, and sagittal) of the uterus is important for determining anatomy and allowing the findings to be standardized, and for evaluating and diagnosing different pathological conditions in clinical practice. Examination of the coronal plane is an important step in identifying uterine pathologies and their relationships to the endometrial canal. Three‐dimensional (3D) ultrasound reveals the normal anatomy better and improves the depiction of abnormal anatomy, as the coronal plane of the uterus can easily be obtained using 3D reconstruction techniques. Our pictorial essay demonstrates that adding 3D ultrasound to a routine gynecological workup can be beneficial for clinicians, enabling a precise diagnosis to be made. In addition, the volumes obtained and stored by 3D ultrasound can allow students or residents to become more familiar with normal and abnormal pelvic structures. Clin. Anat. 31:373–379, 2018. © 2017 Wiley Periodicals, Inc.     

DECREASING PREVALENCE OF THE ACUTE/SUBACUTE CLINICAL FORM OF PARACOCCIDIOIDOMYCOSIS IN MATO GROSSO DO SUL STATE,BRAZIL

With the objective to evaluate the behavior of paracoccidioidomycosis in the last three decades, clinical and epidemiological data of 595 patients admitted to clinical services of the Federal University of Mato Grosso do Sul from 1980 to 2009 were investigated. Gender, age distribution, clinical form, comorbidity with tuberculosis or AIDS, and mortality were compared by decades of clinical admission. It was shown that during the three decades there was a decrease in women percentage, and the same manner occurred a reduction in participants in the age group of 20 to 39 years. Moreover, the acute/subacute forms have been diminished in the period. These fluctuations are closely related and can be simultaneously analyzed. Increased AIDS co-infection prevalence from the first to the second decade was also revealed, coinciding with the appearance of the retroviral epidemic and stabilizing during the third decade. No change in the tuberculosis co-infection rate was observed (overall = 6.9%). It reinforces the importance of this co-morbidity. The overall mortality rate remained steady at 6.7%, not varying significantly from one decade to another. The persistent mortality rate calls attention to the importance of this neglected disease.     

Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non‐MDR paclitaxel resistant ovarian cancer lines ES‐2/TP, MES‐OV/TP and OVCAR‐3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti‐human CCL2 antibody CNTO 888 and the anti‐mouse MCP‐1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.     

Exposure to a farming environment has allergen-specific protective effects on TH2-dependent isotype switching in response to common inhalants

BACKGROUND: IgE synthesis by human B cells results from allergen-dependent, T(H)2-mediated isotype switching. Exposure to a farming environment protects against IgE responses. OBJECTIVE: We reconstructed allergen-dependent switching patterns in vivo to identify the level or levels at which farm exposure acts to protect against atopy. METHODS: Serum IgG1 to IgG4 and IgE to grass (rPhl p 1 and rPhl p 5), cat (rFel d 1), and mite (rDer p 2) were assessed by means of ELISA in the Allergy and Endotoxin study population (812 children). Farm exposure was defined as currently living on a farm, exposure to stables/farm milk in the first year of life, or both. RESULTS: Farm exposure did not affect allergen-specific IgG2 and IgG3 levels but had complex allergen-specific effects on IgG1, IgG4, and IgE levels. Exposure protected against grass-specific responses at every step along the IgG1/IgG4/IgE switching pathway but had no significant effect on mite responses. Protection from cat responses was concentrated at the IgG1 level. For all allergens, failure to express IgG1 was associated with low prevalence of IgG4 or IgE responses. Notably, coexpression of IgG1, IgG4, and IgE to grass was associated with increased risk of allergic disease and higher IgE levels compared with production of IgG1 and IgE without IgG4, suggesting IgG4 coexpression marks stronger activation of T(H)2-dependent events. CONCLUSION: The protective effects of farm exposure were confined to T(H)2-dependent IgG1, IgG4, and IgE expression and were allergen and switch stage specific, suggesting that distinct mechanisms regulate individual steps within allergen-induced class switching in vivo. CLINICAL IMPLICATIONS: Environmental interventions to prevent IgE expression might need to be tailored to specific allergens.