Preinvasive Stage Research Articles

CERVICAL SMEAR ABNORMALITIES IN HIV INFECTED WOMEN ATTENDING A RURAL HOSPITAL ART CENTER IN TAMILNADU

INTRODUCTION: Cervical cancers are the most common form of cancer encountered in Indian women. Studies from India had reported HIV positive women are 10-11 times more prone for cervical carcinomas than HIV negative women with a recent rise in incidence observed. India started a free antiretroviral therapy (ART) program in 2004 with services extended to rural General Hospitals. Cancer cervix can be diagnosed at a preinvasive stage with repeatative papanicolaou smear (cytological screening) and can be readily preventable. AIM: Our aim is to determine the prevalence of PAP smear abnormalities among HIV infected women from rural areas coming for ART initiation and the relationship between immunological status and smear abnormalities. METHODS: As per the Indian National ART program all HIV positive women of reproductive age should undergo PAP smear examination before initiation of ART. All consenting women >18 years of age with history of penetrative vaginal intercourse undergo PAP smear examination. In this observational cohort from 25th June 2011 to 15th January 2012 conducted in Melur ART centre and the cytological reports and the patient clinical and immunological status data was analyzed by using SPSS 17 version. RESULTS: 102 PAP smears were obtained and classified according to Bethesda classification. Five patients (4.90%) were abnormal. Squamous cell carcinoma was observed in 1 (0.98%) patient with a CD4 count of 580 cells/mm3. High squamous intraepithelial lesions were observed in 2 patients (1.96%) with CD4 counts of 208 & 633 cells/mm3 respectively. Low squamous intraepithelial lesion were observed in 2 patients (1.96%) with CD4 counts of 50 and 385 respectively cells/mm3. Immunological status (CD4 count) correlated with grade of the initial lesion (p=0.10). All the patients with PAP smear abnormalities were referred to Madurai Medical College Hospital for further treatment and follow-up. CONCLUSION: In our observational study increasing cytological abnormalities in the HIV Infected women were noted. Accordingly, all ART centre and HIV treatment programs should institute comprehensive reproductive health care services for this high-risk groups, including routine Papanicolaou smear screening

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells\u2019 heterogeneity

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

POSTMENOPAUSAL BLEEDING

Objective : To evaluate the etiology, incidence of malignancy and interval between menopause and onset of abnormal vaginal bleeding inpostmenopausal women. Design: Prospective study. Place And Duration of Study: The study was conducted at Bahawal Victoria Hospital,Bahawalpur for a period of 14 months (February 2002 to March 2003). Subjects: Thirty five cases of postmenopausal bleeding. Methods: Adetailed history was taken followed by a detailed general physical, abdominal, pelvic and per-rectal examination. Cervical pap smear was donein all the patients except those with obvious cervical growth. Besides routine laboratory work, abdominal ultrasonography was done in all thecases. All patients were invariably subjected to fractional curretage and cervical biopsy was taken where indicated. Results: Malignancy wasfound to be the most common cause (51.42%) of postmenopausal bleeding. Carcinoma of the cervix was commonest and found in 34.28%,carcinoma of endometrium in 11.42%, atrophic endometrium in 11.42%, polyps in 8.57%, chronic cervicitis in 8.57%, endometrial hyperplasiain 5.71%, carcinoma of ovary in 2.85%, liomyosarcoma in 2.85%, senile vaginitis, trauma, and forgotten IUCD each in 2.85% of cases. Etiologyremained undetermined in 5.71 % cases. Malignancy was directly related to years of clear span and was 88.88% in cases presenting 10 yearsor more after the menopause. Conclusion: Carcinoma of cervix was the commonest cause of postmenopausal bleeding in our study. Screeningprogramme for early detection of carcinoma of cervix at a pre-invasive stage is highly recommended.

A comparative study of Pap smear cytology and histopathology of cervix biopsy

Background: Carcinoma cervix is one of the leading causes of death of the female population in developing countries. By virtue of its accessibility, cancer of the cervix can be readily diagnosed even in its preinvasive stage. If treated in the earlier stages the patient can often be cured of the disease. Carcinoma of the cervix is the fourth most frequent cancer in women worldwide and the leading cause of death from cancer in several developing countries including India. The use of cervical smear (Papanicolaou/Pap) as a screening tool has significantly reduced the incidence of cervical cancer. The present study has been carried out to evaluate the pattern of cervical cytology and its correlation with histopathological findings. Materials and Methods: The present study was carried out in the department of pathology in a tertiary care hospital over a period of two years. In the two year study period, 2568 pap smears were received. Among these, 194 abnormal smears were identified and they were categorized under The Bethesda System 2014. The histopathological examination of biopsy cervix results of the smears was compared and analyzed. Results: Out of 194 smears studied, reactive changes was 69 (35.57%). Atypical squamous cells of undetermined significance were 47 (24.23%). Low grade squamous intraepithelial lesions were 3 (1.55%) and high grade squamous intraepithelial lesions were 29 (14.95%). Atypical endocervical cells were 2 (1.03%). Atypical endocervical cells favor neoplastic was 4 (2.06%) and endocervical adenocarcinoma in situ was 1 (0.5%). Squamous cell carcinoma was 39 (20.10%). The histopathological examination of biopsy cervix results of the above smears was compared and analyzed. In the histopathological examination results, non-neoplastic lesions were 90 (46.4%), premalignant lesions were 31(16%) and malignant lesions were 73 (37.6%). Conclusion: This correlative study of Pap smear and histopathological examination of the cervix revealed the overall sensitivity of 97%, the specificity of 74% and an accuracy of 87%. The false-negative and false-positive cases in this study can be minimized by proper sampling, screening, interpretation and further follow up study of repeat smears.

Abstract P3-08-19: Biomarkers associated with dcis related breast cancer death

Abstract Introduction In primary ductal carcinoma in situ of the breast (DCIS) tumour biological features associated with risk of invasive recurrence and metastasis may already be present at the pre-invasive stage. The aim of this study was to investigate the correlation of biological markers in DCIS and the risk of subsequent breast cancer death. Patients and methods A nested case-control study was conducted in a population based cohort of women diagnosed with primary DCIS between 1992 and 2012. Women who later died from breast cancer were identified. Four controls per case were selected randomly by incidence density sampling from the same cohort. Tumour blocks were retrieved for histopathological reevaluation and immunohistochemical analysis (IHC) of Oestrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Receptor 2 (HER2) and Ki67 expression. Odds ratios (OR) for risk of breast cancer death with 95% CI was calculated using conditional logistic regression. Results From a cohort of 6964 women with primary DCIS, tumour specimens were available for 66 patients who died from breast cancer and these were compared to samples from 195 controls. DCIS with intense lymphocytic infiltration was associated with an increased risk of breast cancer related death in univariate analysis (OR 2.25; 95%CI 1.02-4.99). None of the biomarkers were individually related to increased risk. In multivariable analysis and stepwise adjusting for age, tumour size and treatment; PR negativity in combination with lymphocytic infiltration (OR 4.40; 95%CI 1.20-16.14), PR negativity, lymphocytic infiltration and presence of comedonecrosis (OR 5.48; 95%CI 1.71-17.57) and the combination of PR negativity, lymphocytic infiltration, comedonecrosis and HER2 positivity (OR 7.54; 95%CI 2.00-28.43) were all independently associated with increased risk of breast cancer related death. Conclusion In the present study, the combination of PR negativity and periductal lymphocytic infiltration was associated with risk of breast cancer related death after primary DCIS. Combining biomarker expressions in DCIS with features in the peritumoural stroma may be useful tools for prognostication. Citation Format: Charlotta Wadsten, Johan Hartman, Irma Fredriksson, Hans Garmo, Fredrik Wärnberg, Malin Sund. Biomarkers associated with dcis related breast cancer death [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-19.

Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRNAs.

The presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation of adaptive immunity and induction of programs related to innate immunity and response to danger signals triggered by activating transcription factor 3. Transcriptional reprogramming was paralleled by the expansion of myeloid populations at the expense of erythroid and B lymphoid fractions. Hematopoietic changes were associated with modifications of the bone marrow stromal architecture through relocalization and increased density in the interstitial area of Nestin+ mesenchymal cells expressing CXCL12 and myeloid cells expressing CXCL12 receptor CXCR4. These early events were concomitant with deregulation of circulating miRNAs, which were predicted regulators of transcripts downregulated in the bone marrow and involved in lymphoid differentiation and activation. These data provide a link between sensing of peripheral cancer initiation by the bone marrow and hematopoietic adaptation to distant noxia through transcriptional rewiring toward innate/inflammatory response programs. SIGNIFICANCE: The bone marrow senses distant tissue transformation at premalignant/preinvasive stages, suggesting that circulating messengers, intercepted in the blood, could serve as early diagnostic markers.

Role of Adiponectin in Cervical Cancer.

Cervical Cancer (CC) is the most common leading cancer in women globally. This is considered to be the type of cancer that is restricted to women. Any women in the reproductive age range can develop CC. However, women between the ages of 25 and 39 are at a higher risk. In comparison with developed countries, the screening and awareness of CC in developing countries are significantly low. Infection with Human papillomavirus (HPV) is the main cause of CC, especially HPV-16 and HPV-18. Other than HPV, there are other factors that can contribute to CC, such as Human simplex virus (HSV) infection and immunocompromised patients with HIV. Cervical cancer can be detected by molecular techniques such as (1) PCR, (2) visual acetic acid method, (3) DNA Hybrid II test, (4) liquid-based cytology, (5) Pap-Smear techniques, and (6) colposcopy techniques. Early detection of CC is very much needed; cryotherapy or LEEP (Loop electro surgical excision procedure) can be conducted during the pre-invasive stage of CC. Some metabolic changes in the human body such as fluctuating levels of insulin and triglycerides and increased activity of adiponectin may lead to CC. These contributing factors, such as adipokines, can be used as biomarkers for CC detection.

Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

BackgroundTumor stroma, of which fibroblasts are the most abundant cell, resembles a non‐healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease‐free survival (DFS), and overall survival (OS).MethodsIn a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin‐antithrombin (TAT) and D‐dimer were correlated with clinicopathological data, and 5‐year survival.ResultsFibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER‐ (vs ER+), and HER2+ (vs HER2‐) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D‐dimer was higher in node positive (507 (CI: 411‐625) ng/mL, n = 68) vs negative patients (428 (CI: 387‐472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16‐3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3‐fold mortality risk compared to low TAT.ConclusionThis demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

Abstract PR14: Preclinical models to dissect immune escape in pancreatic cancer

Abstract Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis and efforts to harness immune-based therapies are in high demand. Using retrograde pancreatic duct instillation of lentiviral particles, we have established and characterized a preclinical autochthonous mouse model for immunogenic PDAC. Specifically, pancreatic tumors are initiated in KRASLSL-G12D/+; p53flox/flox (KP) mice using lentiviral particles expressing Cre recombinase and a tumor-specific antigen (TSA) to track the endogenous antigen-specific T cell response in both precursor lesions (PanIN) and adenocarcinoma (PDAC). Using this model system, we demonstrate profound immunoediting in the autochthonous pancreas, which occurs primarily at the preinvasive (PanIN) stage. In parallel, we derived a biologic library of immunogenic or nonimmunogenic pancreatic organoids and developed an ex vivo co-culture system of pancreatic organoids with antigen-specific CD8 T cells that recapitulates the phenomena of immunoediting. Additionally, we examined the effect of TSA expression in established adenocarcinomas and performed preclinical trials in which the CD8 T-cell compartment was transiently depleted and then restored, to evaluate at what point during tumor progression pancreatic tumors gain the ability to evade immune clearance. Intriguingly, we identified both “regressor” tumors as well as “progressor” tumors in response to CD8 restoration. Longitudinal imaging was paired with flow cytometric analysis to track both clinical and antigen-specific T-cell responses. Excitingly, we found that a subset of “regressor” tumors undergo a complete pathologic response following CD8 T-cell restoration, highlighting the translational potential for novel insights regarding immune escape in PDAC. In addition, we demonstrate that both the magnitude and kinetics of the antigen-specific T-cell response tracks with the clinical response of these tumors, with “progressor” tumors eliciting both delayed kinetics and a blunted response compared with “regressor” tumors. Additionally, we developed an immunogenic genetically defined organoid system in which KP organoids were engineered to express a defined neoantigen from a safe harbor locus. In line with prior studies, a subset of immunogenic organoids was completely rejected upon orthotopic transplantation and this clearance was dependent upon CD8 T cells. However, in contrast to observations using two-dimensional monolayer cell lines, we also identified a significant subset of orthotopically transplanted immunogenic pancreatic organoids that successfully evade immune clearance, despite eliciting an antigen-specific immune response. Immunophenotyping the tumor microenvironment revealed that antigen-specific CD8 T cells within these “escaper” tumors display hallmarks of T-cell exhaustion. These complementary systems now provide a robust preclinical platform to rapidly interrogate potential therapeutic interventions. This abstract is also being presented as Poster C17. Citation Format: William A. Freed-Pastor, Laurens Lambert, Ana P. Garcia, George Eng, Omer Yilmaz, Tyler Jacks. Preclinical models to dissect immune escape in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR14.

Abstract B31: Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis

Abstract Dendritic cell (DC) dysregulation in cancer has long been hypothesized to be a tumor-associated phenomenon. Using the KPC autochthonous mouse model of pancreatic ductal adenocarcinoma, we reveal that dysfunction of type 1 conventional DCs (cDC1s)—critical mediators of antitumor T-cell immunity—instead develops in the preinvasive stage of carcinogenesis and impacts the host systemically prior to malignancy. Both cDC1 survival and function are impacted, with cDC1s suspended in a state of semi-maturation in which genes involved in response to inflammation and proteasomal degradation are successfully upregulated while genes encoding T cell-polarizing cytokines necessary for T-cell activation fail to be induced. cDC1 dysfunction subsequently impairs CD8+ T-cell activation in vivo. However, this defect remains reversible even following progression to invasive cancer. CD40 activation induces an IFNg response signature that drives cDC1 maturation and migration to draining lymph nodes, restoring CD8+ T-cell activation to normal levels. This study therefore reveals the unexpected depths of cDC1 dysregulation in carcinogenesis but nevertheless elaborates therapeutically tractable strategies towards cDC1 repair. Citation Format: Jeffrey H. Lin, Austin P. Huffman, Emma E. Furth, Robert H. Vonderheide. Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B31.

Protein Expression of PTTG-1, OCT-4, and KLF-4 in Seminoma: A Pilot Study.

Seminomas are the most frequent kind of testicular germ cell tumors (TGCTs), accounting for 50% of tumor diagnosis in young men, whereas non-seminomas account for 40% and mixed forms for 10% of cases. It is currently supposed that TGCTs evolve from a pre-invasive stage of carcinoma in situ (CIS). Octamer-binding transcription factor 4 (OCT4) is essential for self-renewal of stem cells. It is considered as a major regulator of cell pluripotency. Prior studies have shown that seminoma expresses OCT4. Transcription factor Krüppel-like factor 4 (KLF4) has moreover associated with embryonic stem cell maintenance. Finally, we previously demonstrated the expression of PTTG1 in CIS and seminomas. In this pilot study, we compared the combined expression of PTTG1 with KLF4 and OCT4 in seminoma, in order to validate our hypotesis that PTTG1 marks a specific population of stem cells in neoplastic tissue, strictly related with tumor. Formalin-fixed and paraffin-embedded testicular tissues by 5 patients who underwent an orchidectomy for seminoma have been collected and immunofluorescence analysis was performed using antibody rabbit monoclonal PTTG-1 and mouse monoclonal OCT4 or mouse monoclonal KLF4 antibody. In seminoma we observed that tumor cells strongly express OCT-4 in all seminomas and in the intratubular areas of seminoma. Expression of KLF-4 was observed in many tumor cells. PTTG1 marks some specific OCT4- and KLF4-positive tumor cells, mainly localized at the periphery of the neoplasm. In the intertubular infiltration areas nests of cells expressing both OCT4/KLF4 and PTTG1 have been observed. This is the first identification of a cell population in seminoma characterized for being OCT4, KLF4, and PTTG1 positive cells in seminoma, associated with cancer invasiveness. Further investigation is needed to elucidate if a functional abrogation of PTTG1 might be used in order to offer new therapeutic approaches in the clinical workout of seminoma.

Arabidopsis GCN2 kinase contributes to ABA homeostasis and stomatal immunity

General Control Non-derepressible 2 (GCN2) is an evolutionarily conserved serine/threonine kinase that modulates amino acid homeostasis in response to nutrient deprivation in yeast, human and other eukaryotes. However, the GCN2 signaling pathway in plants remains largely unknown. Here, we demonstrate that in Arabidopsis, bacterial infection activates AtGCN2-mediated phosphorylation of eIF2α and promotes TBF1 translational derepression. Consequently, TBF1 regulates a subset of abscisic acid signaling components to modulate pre-invasive immunity. We show that GCN2 fine-tunes abscisic acid accumulation and signaling during both pre-invasive and post-invasive stages of an infection event. Finally, we also demonstrate that AtGCN2 participates in signaling triggered by phytotoxin coronatine secreted by P. syringae. During the preinvasive phase, AtGCN2 regulates stomatal immunity by affecting pathogen-triggered stomatal closure and coronatine-mediated stomatal reopening. Our conclusions support a conserved role of GCN2 in various forms of immune responses across kingdoms, highlighting GCN2’s importance in studies on both plant and mammalian immunology.

TUBB4B Downregulation Is Critical for Increasing Migration of Metastatic Colon Cancer Cells.

Tumor metastasis, the major problem for clinical oncology in colon cancer treatment, is linked with an epithelial-mesenchymal transition (EMT). The observed cellular transformation in this process is manifested by cell elongation, enhanced cell migration and invasion ability, coordinated by cytoskeleton reorganization. In the present study, we examined the role of tubulin-β4 (TUBB4B) downregulation that occurs during EMT in colon cancer cells, in the modulation of the function of microtubules. Based on biochemical and behavioral analysis (transmigration) we posit that the decrease of the TUBB4B level is critical for microtubule-vimentin interaction and contributes to the maintenance of polarity in migrating cells. The microscopic studies revealed that TUBB4B decrease is accompanied by cell elongation and increased number of matured focal adhesion sites, which is a characteristic of the cell metastatic stage. We also demonstrated faster polymerization of microtubules in cells with a lower level of TUBB4B. Simultaneous TUBB3 upregulation, reported during EMT, acts additively in this process. Our studies suggest that the protein level of TUBB4B could be used as a marker for detection of the preinvasive stages of the colon cancer cells. We also concluded that chemotherapy enriched to increase TUBB4B level and/or to stabilize microtubule polymerization might more effectively prevent metastasis in colon cancer development.

Role of bronchoscopy in management of central squamous cell lung carcinoma in situ.

Squamous cell carcinoma in situ (SCIS) is the pre-invasive stage of squamous cell carcinoma. Early detection and management of SCIS can prevent further progression. Although surgery and external beam radiation therapy are treatment options for SCIS, smaller lesions can be easily managed by bronchoscopic modalities like photodynamic therapy (PDT), cryotherapy, mechanical debulking with biopsy forceps, electrocautery and argon plasma coagulation (APC). Endobronchial brachytherapy (EBBT) and lasers may be judiciously utilized in selected cases. Although, previous studies of treatment modalities may have inadvertently included cases of invasive carcinomas, the advent of new technologies like radial probe endobronchial ultrasound (RP-EBUS) and optical coherence tomography (OCT) can help accurately determine the of depth of invasion. Superficial extent can also be better demarcated with techniques like auto-fluorescence bronchoscopy and narrow band imaging (NBI). New drugs for PDT with deeper penetration and less phototoxicity are being developed. These advances hopefully will allow us to perform superior clinical trials in future and improve our understanding of diagnosis and management of SCIS.

Abstract 5031: Regulatory T cell ablation accelerates early stage breast cancer progression

Abstract Breast cancer is the most common malignancy in women worldwide. Early detection of pre-invasive breast tumor has dramatically improved due to the routine screening for women. Ductal carcinoma in situ is a non-obligate precursor of breast cancer, and it only progresses to invasive breast cancer in about 40% of patients. We have previously shown that transient ablation of regulatory T (Treg) cells in established breast tumors results in significant reduction of primary and lung metastatic tumor growth. In this study, we aim to investigate the specific role of Treg cells at the pre-malignant stages. Using a spontaneous, stage-wise MMTV-driven polyoma middle T (PyMT) model of murine mammary carcinogenesis, crossed to Foxp3DTR knock-in mice where injection of diphtheria toxin leads to a complete ablation of Treg cells for around 7 days, we found that ablation of Treg cells at the pre-invasive tumor stage resulted in a significant increase in the number of mammary glands developing tumors, as well as tumor growth compared to control mice. Histological examination of tissues revealed that the area of the incipient tumors was larger in Treg cell-ablated mice, and presented a more advanced tumor stage. In addition, Treg cell ablation resulted in a pronounced mammary inflammatory infiltrate, including an increase in tumor-associated macrophages and a soluble cytokine network conducive to tumor progression. Interestingly, Treg cell ablation increased the percentage of cancer stem/progenitor cells in the mammary compartment. Overall, our study demonstrates that unlike their role in established cancers, Treg cells ablation promotes breast cancer progression at early stages. Citation Format: Wei Du, Leandro Martinez, Valentina Robila, Nicholas Clark, Michael Idowu, Paula Bos, Paula Bos. Regulatory T cell ablation accelerates early stage breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5031.

Clinico-pathological study 200 cases of Breast lesions in a tertiary care centre of Rohtas, Bihar, India

Background: Breast cancer is the second most common cancer in Indian women. The incidence of Breast cancer in India is increasing slowly and has bad prognosis if detected in late stages. But, its incidence can be decreased if its detection is made at earliest stages, i.e. in the preinvasive stage. This present study was undertaken to assess clinico-pathological aspect of breast lesions in a tertiary care centre of Rohtas, Bihar. Material and Methods: A retrospective study was conducted in the department of Pathology, NMCH, Jamuhar, Sasaram. The data was collected form medical records department. The study period was of two years from January, 2017 to December, 2018 after approval from institutional ethics committee. Results: A total of 200 cases of breast lesions were analyzed. The ratio of benign to malignant lesions was 3.9:1. The overall mean age of patients with breast lesion was 34.5 years. Among 20.5% malignant cases, the age group affected most was 41-50 years. Only 6% of breast lesions were of inflammatory nature. This result is less as compared to past studies and all the lesions histologically were of chronic non-specific mastitis. The most common type of malignancy observed was invasive carcinoma of no special type (NST). Conclusion: The pattern of breast lesions provides valuable information regarding clinic-pathological profile of patients. The clinical diagnosis of breast lesions should be correlated with histopathological features for correct and adequate management of the case.

Immune evasion before tumour invasion in early lung squamous carcinogenesis

Early detection and treatment are critical for improving the outcome of patients with cancer1. Understanding the largely uncharted biology of carcinogenesis requires deciphering molecular processes in premalignant lesions, and revealing the determinants of the intralesional immune reaction during cancer development. The adaptive immune response within tumours has previously been shown to be strongest at the earliest stage of carcinoma2,3. Here we show that immune activation and immune escape occur before tumour invasion, and reveal the relevant immune biomarkers of the pre-invasive stages of carcinogenesis in the lung. We used gene-expression profiling and multispectral imaging to analyse a dataset of 9 morphological stages of the development of lung squamous cell carcinoma, which includes 122 well-annotated biopsies from 77 patients. We identified evolutionary trajectories of cancer and immune pathways that comprise (1) a linear increase in proliferation and DNA repair from normal to canceroustissue; (2) a transitory increase of metabolism and early immune sensing, through the activation of resident immune cells, in low-grade pre-invasive lesions; (3) the activation of immune responses and immune escape through immune checkpoints and suppressive interleukins from high-grade pre-invasive lesions; and, ultimately, (4) the activation of the epithelial-mesenchymal transition in the invasive stage of cancer. We propose that carcinogenesis in the lung involves a dynamic co-evolution of pre-invasive bronchial cells and the immune response. These findings highlight the need to develop immune biomarkers for early detection as well as immunotherapy-based chemopreventive approaches for individuals who are at high risk of developing lung cancer.

Cervical Cancer, Different Treatments and Importance of Bile Acids as Therapeutic Agents in This Disease.

Cervical cancer can be cured, because it has a long preinvasive period. Early diagnosis and treatment of cervical cancer at women are crucial for reducing of rate mortality. Today, there are many methods for detecting premalignant lesions and one of them is a conventional Papanicolaou test. Cervical cancer develops through a series of changes in the epithelium called cervical intraepithelial neoplasia (CIN). The biological and genetic characteristics of the cells at cancer in situ are irreversibly altered and abnormal cells have the potential to metastasize to others anatomical regions. Infection with human Papillomavirus, which is transmitted sexually, is considered the main cause and represent the necessary, but not the only factor for the development of cervical cancer. Types of high risk human Papillomavirus are often associated with invasive cervical cancer. The carcinogenic types of HPV 16 and 18 are responsible for 70% of cervical cancer and about 50% of CIN 3. Primary prevention of cervical cancer is aimed at reducing incidence, control of causes and risk factors. In this scientific work, in addition to explaining the various treatments necessary for the treatment of cervical carcinoma, we were discussed about the anticancer effects of the synthetic derivative of ursodeoxycholic acid, such as HS-1183, and synthetic derivatives of chenodeoxycholic acid such as HS-1199 and HS-1200. Also, the effects of bile acid complexes with metals such as platinum, zinc, nickel, and copper were considered in the effective treatment of cervical cancer.KEY POINTS• Lymphogenic spreading of cervical cancer occurs relatively early in the regional lymph nodes, while this sort of progression of cervical cancer is rarer in the juxtaregional (paraaortic), mediastinal and supraclavicular nodes.Clinically proven supraclavicular metastases are not a rarity. In stages IIb and IIIa with metastases in paraaortal nodes occur a 20% metastases at the neck lymph nodes.Hematogenic metastases are relatively rare and occur in the posterior phase. Distant metastases are detected in the lungs and liver.Preinvasive and microinvasive stages of cervical cancer are without symptoms. With deeper invasion of the strome, certain clinical symptoms such as prolonged menstruation, increased vaginal secretions, vaginal bleeding between the two periods, contact bleeding (after coitus), unilateral pelvic pain with spreading in hip joint (infiltration of the pelvic nerve plexus), dysuric disturbance, anemia, islet of the lower extremities.In order to diagnose the level spreading of primary lesion of cervical cancer most commonly are used the supplemental searches such as cytoscopy, rectoscopy, urography, irigography, lung and bone radiography, scintigraphy of the liver, kidney and bone, lymphography, CT (MR) of abdomen and pelvis, as well as laboratory analysis.Surgical treatment consists of transvaginal hysterectomy, transabdominal removal of the uterus (via laparotomy), bilateral adenectomy (removal of the ovaries and the fallopian tubes), upper and middle third of the vagina and lymphonodectomy of the regional lymph nodes. The most commonly used radiotherapy, intracavitary brachytherapy, manual afterloading technique and remote afterloading techniques.The synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid such as HS-1183, HS-1199, and HS-1200 are used to treat cervical cancer. These derivatives of chenodeoxycholic acid and ursodeoxycholic acid are capable of inhibiting cell proliferation and inducing apoptosis in SiHa human cells of cervix.Platinum compounds are used as catalysts in cervical cancer therapy. Clinical use of platinum complexes for which the bile acids bind is based on the desire to achieve the death of tumor cells and the spectrum of drug activity in the treatment of cervical cancer.Bisursodeoxycholate (ethylenediamine) platinum (II) [Pt(UDC)2(en)] is characterized by important cytotoxicity against HeLa cervical carcinoma cells and this effect already being clearly detectable after 24 h.

Morphological classification of pre-invasive lesions and early-stage lung adenocarcinoma based on CT images

To retrospectively analyze the computed tomography (CT) features in patients with pre-invasive lesions and early-stage lung adenocarcinoma and to explore the correlation between tumor morphological changes and pathological diagnoses. CT morphological characteristics in 2106 patients with pre-invasive (stage 0) and early-stage (stage I) lung adenocarcinoma were analyzed; lesions were confirmed by surgical pathology. Based on the morphological characteristics, the lesions were divided into eight types: I (cotton ball, ground-glass nodules), II (solid fill), III (granular), IV (dendriform), V (bubble-like lucencies), VI (alveolate or honeycomb), VII (scar-like), and VIII (notched or umbilication). The different distributions of eight morphological types in pathological types of the lesions and subtypes of invasive adenocarcinoma were analyzed by chi-squared or Fisher's exact test. Correlation between the percentage of ground-glass opacity in the lesions and pathology types were analyzed by two-tailed Pearson's test. A negative correlation was observed between the pathological types and proportion of ground-glass component in the lesions (p < 0.001 and r = - 0.583). Significant differences in morphological characteristics among various pathological types of pre-invasive lesions and early lung adenocarcinomas were observed (p < 0.05). Furthermore, among the different pathological subtypes of stage I invasive adenocarcinoma, the differences in their manifestation as morphological types I, II, III, and VI were statistically significant (p< 0.05). The eight types of morphological classification of pre-invasive lesions and early-stage (stage 0 or stage I) lung adenocarcinoma has different pathological bases, and morphological classification may be useful for the diagnosis and differential diagnosis of lung adenocarcinoma. • CT morphological classification of pre-invasive lesions and lung adenocarcinoma is intuitive. • CT morphological classification characterizes morphological changes of the entire lesion. • Different pathological types of lung adenocarcinoma have different morphological features.

Uncommon Intraluminal Tumors of the Gallbladder and Biliary Tract: Spectrum of Imaging Appearances

Intraluminal pathologic conditions of the bile ducts and gallbladder are common, most frequently consisting of calculi and adenocarcinoma. In recent years, intraductal papillary neoplasm of the bile ducts (IPN-B), which is analogous to intraductal papillary mucinous neoplasm of the pancreas, has been recognized as a distinct pathologic entity and a precursor lesion to adenocarcinoma of the bile ducts. Intraductal tubulopapillary neoplasm (ITPN) of the bile duct was subsequently described as a distinct pathologic entity. With increased awareness and advances in imaging techniques, these lesions are diagnosed with increased frequency at preoperative imaging. A similar neoplasm in the gallbladder is referred to as intracholecystic papillary neoplasm. These lesions are often diagnosed at a preinvasive stage and have a better prognosis than invasive cholangiocarcinoma when treated with curative resection, underscoring the importance of an accurate imaging diagnosis. The most common causes of polypoid lesions of the gallbladder are cholesterol polyps and adenomyomatosis. These lesions need to be differentiated from the less common but clinically important adenocarcinoma of the gallbladder. Imaging is crucial to identify polyps that are at high risk for malignancy so that the appropriate management choice between imaging follow-up and cholecystectomy can be made by the treating physicians. Other less common gallbladder tumors, such as gallbladder adenomas, lymphoma, and metastases to the gallbladder, can manifest as intraluminal tumors; and awareness of these lesions is also important. In this article, the recent literature is reviewed; and the imaging appearances, histopathologic findings, and management of uncommon intraluminal tumors of the bile ducts and gallbladder and their mimics are discussed. ©RSNA, 2019.