Gut mucus layer degradation is associated with aggressive cervical cancer phenotype

Background Gut microbiome community composition differs between cervical cancer (CC) patients and healthy controls, and increased gut diversity is associated with improved outcomes after treatment. We proposed that functions of specific microbial species adjoining the mucus layer may directly impact the biology of CC. Results In this study, we examined metagenomes of rectal swabs in 41 CC patients using whole-genome shotgun sequencing and found a significant association between molecular functions encoded by the metagenomes with markers of aggressive cancer including initial tumor size and stage. Profiling of the molecular function abundances and their distributions identified 2 microbial communities co-existing in each metagenome but with distinct metabolism and taxonomic structures. Community A (Clostridia and Proteobacteria predominant) was characterized by high activity of pathways involved in stress response, mucus glycan degradation and utilization of degradation byproducts. This community was prevalent in larger, advanced stage tumors. Conversely, community B (Bacteroidia predominant) was characterized by fast growth, active oxidative phosphorylation, and production of vitamins. This community was prevalent in small, early-stage tumors. Conclusions Based on these results, we propose that increased mucus layer degradation is associated with a more aggressive cervical cancer phenotype.

Hearing loss and volumetric growth rate in untreated vestibular schwannoma

OBJECTIVE In this study, the authors aimed to clarify the relationship between hearing loss and tumor volumetric growth rates in patients with untreated vestibular schwannoma (VS). METHODS Records of 128 treatment-naive patients diagnosed with unilateral VS between 2012 and 2018 with serial audiometric assessment and MRI were reviewed. Tumor growth rates were determined from initial and final tumor volumes, with a median follow-up of 24.3 months (IQR 8.5–48.8 months). Hearing changes were based on pure tone averages, speech discrimination scores, and American Academy of Otolaryngology–Head and Neck Surgery hearing class. Primary outcomes were the loss of class A hearing and loss of serviceable hearing, estimated using the Kaplan-Meier method and with associations estimated from Cox proportional hazards models and reported as hazard ratios. RESULTS Larger initial tumor size was associated with an increased risk of losing class A (HR 1.5 for a 1-cm3 increase; p = 0.047) and serviceable (HR 1.3; p < 0.001) hearing. Additionally, increasing volumetric tumor growth rate was associated with elevated risk of loss of class A hearing (HR 1.2 for increase of 100% per year; p = 0.031) and serviceable hearing (HR 1.2; p = 0.014). Hazard ratios increased linearly with increasing growth rates, without any evident threshold growth rate that resulted in a large, sudden increased risk of hearing loss. CONCLUSIONS Larger initial tumor size and faster tumor growth rates were associated with an elevated risk of loss of class A and serviceable hearing.

Mathematical simulation and prediction of tumor volume using RBF artificial neural network at different circumstances in the tumor microenvironment

Uncontrolled proliferation of cells in a tissue caused by genetic mutations inside a cell is referred to as a tumor. A tumor which grows rapidly encounters a barrier when it grows to a certain size in presence of preexisting vasculature. This is the time when it has to find a way to go on the growth. The tumor starts to secrete tumor angiogenic factors (TAFs) and stimulate preexisting vessels to grow new sprouts. These new sprouts will find their way to the tumor in the extracellular matrix (ECM) by the gradient of TAF. As these new capillaries anastomose and reach tumor, fresh oxygen is available for the tumor and it will reinitiate the growth. Number of initial sprouts, distance of initial tumor cells from the vessel(s) and initial density of the tumor at the time of sprout formation are questions which are to be investigated. In the present study, the aim is to find the response of tumor cells and vessels to the reciprocal effects of each other in different circumstances in the tissue. Together with a mathematical formulation, a radial basis function (RBF) neural network is established to predict the number of tumor cells at different circumstances including size and distance of initial tumors from the parent vessel. A final formulation is given for the final number of tumor cells as a function of initial tumor size and distance between a parent vessel and a tumor. Results of this simulation demonstrate that, increasing the distance between a tumor and a parent vessel decreases the number of final tumor cells. Specially, this decrement becomes faster beyond a certain distance. Moreover, initial tumors in bigger domains must become much bigger before inducing angiogenesis which makes it harder for them to survive.

Quantitative Predictions of Neoadjuvant Chemotherapy Effects in Breast Cancer by Individual Patient Data Assimililation

Neoadjuvant chemotherapy has been used for breast cancer aiming at downgrading before surgery. In this article we propose a new quantitative analysis of the effects of the neoadjuvant therapy to obtain numerical, personalized, predictions on the shrinkage of the tumor size after the drug doses, by data assimilation of the individual patient. The algorithm has been validated by a sample of 37 patients with histological diagnosis of locally advanced primary breast carcinoma. The biopsy specimen, the initial tumor size and its reduction after each treatment were known for all patients. We find that: a) the measure of tumor size at the diagnosis and after the first dose permits to predict the size reduction for the follow up; b) the results are in agreement with our data sample, within 10% to 20%, for about 90% of the patients. The quantitative indications suggest the best time for surgery. The analysis is patient oriented, weakly model dependent and can be applied to other cancer phenotypes.

CYR61, a potential biomarker of tumor inflammatory response in epithelial ovarian cancer microenvironment of tumor progress

Background Recent studies have found that inflammatory response is involved in the pathogenesis of ovarian cancer. Advanced ovarian cancer is often presented with ascites that is rich in cytokines, inflammatory factors or cancer cells. Therefore, it is important to study the microenvironment of ascites in order to further clarify the occurrence and progression of ovarian cancer. As a pro-inflammatory factor, the Cyr61 expression patterns are inconsistent in human tumors. Although it has been reported that Cyr61 is related to the progression of ovarian cancer, its specific mechanism is not yet clear. This study sought to evaluate the Cyr61 levels of ascites, serum and different tissues of ovarian cancer to explore the potential association of Cyr61with the tumor-associated inflammatory microenvironment of EOC. Methods Tumor specimens were procured from patients with ovarian serous cystadenocarcinoma and ovarian serous cystadenoma. Cyr61 and IL-6 levels of serum or ascites were determined by ELISA (Enzyme-Linked ImmunoSorbent Assay), while Cyr61 expressions of different ovarian tumor tissues were evaluated by IHC (Immunohistochemistry). Then the correlation of Cyr61 level in ascites with clinicopathologic features was analyzed. And other laboratory data were obtained from medical records. Results Both in ascites and serum, significantly higher Cyr61 levels were found in ovarian serous cystadenocarcinoma. In malignant ascites, higher Cyr61 level of ovarian serous cystadenocarcinoma was more closely associated with FIGO stage, initial tumor size > 10 cm and the residual tumor size. And the increased IL-6 level was linearly related to Cyr61 level. Moreover, the serum levels of Cyr61, IL-6 and CRP in advanced stage of ovarian cancer were much higher than those in early stage. Lastly, the IHC data demonstrate that Cyr61 expression of ovarian serous adenocarcinoma was higher than that of ovarian serous cystadenoma, but it was lower than the paired metastatic lesions. Conclusions As a pro-inflammatory factor, increased ascites Cyr61 level is associated with FIGO stage, initial tumor size > 10 cm and the residual tumor size. Moreover, serum Cyr61 may be used as a potential marker for EOC inflammatory response. Finally, Cyr61 may be involved in the process of tumor metastasis and progression by producing IL-6 and CRP in the EOC inflammatory microenvironment.

P11.22 Radiotherapy effects in GBM Rat model CNS1

BACKGROUND CNS1 is a syngeneic glioma model in Lewis Rats. It is an aggressive infiltrating tumor cell line that mimics important aspects of human GBM such as rapid growth, dispersal along blood vessels and white matter, pseudopallisading cells with features of hemorrhage and necrosis. CNS1 tumors are infiltrated with macrophages and T-cells, and were studied in the context of immunotherapy and gene therapy, extracellular matrix and invasion, but CNS1 response to radiation has not yet been described. If we wish to combine novel immune-based therapies with existing GBM protocols that include radiation and chemotherapy, we will need models that respond to these protocols. As a first step in this direction, we sought to describe CNS1 response to radiation in vitro and in vivo. MATERIAL AND METHODS In vitro, survival of irradiated CNS1 cells was assessed with clonogenic assay. Radiation varied in dose from 0 to 10 Gy and was delivered via Kimtron Polaris X-ray generator. In vivo, male Lewis rats were intra-cranially inoculated with 0.5*106 CNS1 tumor cells and monitored for survival. Treated rats (N=6) were subjected to a single 20Gy whole-head radiation treatment under full anesthesia, delivered five days post-inoculation. Control rats (N=5) were anesthetized but not irradiated. Tumor size was monitored using contrast enhanced T1-weighted MRI in both treated and control rats at several time points (4, 6, 11, 18 and 32 days post tumor inoculation). RESULTS CNS1 cells are sensitive to radiation in vitro, as cell survival decreased after exposure to increasing amounts of radiation. In vivo, while initial tumor size did not significantly differ between groups, rats treated with radiation survived significantly longer than control rats (23.8 ± 5.0 days vs. 11 ± 4.1 days, p<0.005). Growth arrest following irradiation in vivo was not detected 1d after treatment but was observed 6d post-irradiation. Growth arrest was recorded in half of the treated rats, showing no increase in tumor size (N=2) or reduction in tumor volume (N=1) relative to 1d post-irradiation. Tumor growth rates were lower in all irradiated rats relative to control rats. Survival time was negatively correlated with initial tumor size in the control group but not in the treatment group. CONCLUSION CNS1 rat model of GBM is a valid model of radiotherapy effects on GBM tumors. Further studies combining radiation and chemotherapy are the next step. Support for this work was provided by Israel Cancer Association.

The Prognostic Value of Initial Tumor Size in Patients with Ewing Family of Tumors

Introduction: Ewing Family of Tumors (EFT) is a high grade embryonic malignancy, common in children andyoung adults (CYAs). The prognostic factors include initial tumor volume, site, presence of metastasis, and theEWS/FLI 1 mutation. Low volume disease is known to result in higher response rates and longer survival times.Methods: Twelve patients with non-metastatic EFT were managed with the intensive Ewing Family Tumor(EFT 2001) protocol. The patient characteristics studied were - age, sex, site, number of sites involved,bone marrow involvement and size (volume). Tumor volume was measured in non-metastatic tumors by tridimensionalvolume in MRI scans.Results: Progression free survival (PFS) of patients with initial tumor volume ????100 cc ranged from 30 monthsto 74 months (mean 56.4 months) while that for > 100 cc ranged from 19 months to 79 months (mean 40months) (p value: 0.701). However there was trend towards better survival in patients with initial tumor volume????100 cc.Conclusions: There is a trend towards better PFS in patients with smaller tumor volume at presentation. Thusinitial tumor volume is a prognostic factor in Ewing family of tumors.doi:http://dx.doi.org/10.3126/mjsbh.v12i2.12925

Neoadjuvant Conformal Chemoradiation with Induction Chemotherapy for Rectal Adenocarcinoma. A Prospective Observational Study

Background & Aims: The purpose of this prospective observational study was to evaluate the rate andthe prognostic factors for down-staging and complete response for rectal adenocarcinoma after inductionchemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphinctersaving surgery.Methods: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2-4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy.Results:The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p<0.01), cN0 (p<0.01), distance from anal verge >5 cm (p<0.01), initial CEA <6.2 ng/ml (p<0.01), higher number of chemotherapy cycles with Oxaliplatin (pROC=0.05) and protraction of radiotherapy of >35 days (p<0.01). Nine patients from 81 (11.1%) presented complete response (7 pathological and 2 clinical); the independent prognostic factors were stage cT2 versus cT3-4 (p<0.01), initial tumor size ≤3.5 cm and distance from anal verge >5 cm (p=0.03). Sixty-eight patients (79.1%) underwent radical surgery and among them 35 patients (51.5 %) had a sphincter saving procedure.Conclusions: Induction chemotherapy with neoadjuvant chemoradiation produced important down-staging in rectal adenocarcinoma. Independent prognostic factors for T down-staging were: age, cN0, distance from anal verge, initial CEA, the number of Oxaliplatin cycles and duration of radiotherapy; for complete response: cT2, initial tumor size and distance from the anal verge. Abbreviations: 5FU: 5-fluorouracil; AJCC: American Joint Committee on Cancer; AV: anal verge; CAPOX: Capecitabine plus Oxaliplatin; CCR: clinical complete response; CRT: chemoradiation; CTC4.0: Common Terminology Criteria for Adverse Events, version 4.0; ECOG: Eastern Collaborative Oncology Group; EUS: endorectal ultrasound; FOLFOX: 5-fluorouracil plus Oxaliplatin; LARC: locally advanced rectal cancer; PCR: pathological complete response; PS: performance status; PTV: planning target volume; R0: Resection, 0 (microscopically clear resection margin); ROC curve: receiver operating characteristic curve; TME: total mesorectal excision; TRG: tumor regression grade.

Nomogram for predicting breast-conservation surgery after neoadjuvant chemotherapy.

1128 Background: The indications for neoadjuvant systemic treatment (NST) have broadened to early breast cancer patients and more patients can undergo breast conservation with results in better cosmetic outcomes. However, a significant number of patients with operable breast cancer still require mastectomy after NST with a small number of patients experiencing disease progression which may hinder complete surgical resection. Therefore, accurate prediction of each patient’s likelihood of achieving breast conservation after NST is important for establishing a treatment plan for patients with operable breast cancers. Methods: We identified 534 women from the Seoul National University Hospital Breast Care Center, who were stage II and III, and treated with neoadjuvant chemotherapy and surgery from Jan. 2001 to Dec. 2010. Breast conservation surgery (BCS) and tumor size reduction to less than 3cm were clinical outcome variables for nomograms, and we analyzed the various clinicopathologic factors best predicting these outcomes. To develop well-calibrated and exportable nomograms for BCS and for residual tumor size, we built each model in a training cohort and validated it in an independent validation cohort. Results: Of the 513 patients, pCR was observed in 10.5% and BCS was performed in 50.1%. The nomogram for predicting BCS and tumor size reduction to less than 3cm were constructed using logistic regressing model. Initial tumor size(p<0.001), the distance between the lesion and the nipple (p < 0.001), the presence of suspicious calcifications in the mammography (p = 0.0127) and multicentricity (p = 0.0146) were independently associated with breast conservation surgery. ER status (p = 0.001), initial tumor size (p < 0.001), histologic type (p = 0.012) were independently associated with a residual tumor size <3cm. Mastectomy rate in the larger than 3cm tumors were 72.7%, and breast conservation surgery in smaller than 3cm tumors were 63.2%. (p < 0.001). Conclusions: In conclusion, we have established a new model to predict BCS and residual tumor size after NST. The model showed the outperformed prediction accuracy compared with previous similar models with reflecting novel factors impacting on surgical decision making.