recurrent tumors
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2022 ◽  
Author(s):  
Nicole Gull ◽  
Michell Jones ◽  
Pei-Chen Peng ◽  
Simon Coetzee ◽  
Tiago Silva ◽  
...  

Abstract Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P=0.006) in these BRCA1/2 carriers. Conclusions These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.


2021 ◽  
Vol 50 (1) ◽  
pp. 69-73
Author(s):  
A. A. Tsypurdeeva ◽  
A. F. Urmancheeva ◽  
D. R. Zeldovich ◽  
E. F. Kira

To study the possibilities of laparoscopy in diagnosis of malignant ovarian tumors 635 patients at different stages of the disease were examined. High informing characteristics make it possible to recommend laparoscopy as a method of improved diagnostics of tumors in smallpelvic with the aim of early revealingof malignant tumors, morphologic verification and evaluation of tumor extensiveness, diagnosis of preclinical recurrent tumors in case of diverse results of non-invasive monitoring methods.


MD-Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 22-31
Author(s):  
G. F. Allakhverdiyeva ◽  
A. M. Mudunov ◽  
P. A. Zeynalova ◽  
T. Yu. Danzanova ◽  
A. F. Batsev

The study objective is to establish the capabilities of ultrasound (US) examination in evaluation of the advancement of squamous-cell carcinoma of the larynx and hypopharynx compared to histological examination and other diagnostic methods.Materials and methods. US examination was performed in 86 patients with squamous-cell carcinoma of the larynx and hypopharynx. The study included 14 (16.3 %) patients with stage I disease, 29 (33.7 %) patients with stage II, 19 (22.1 %) patients with stage III and 24 (27.9 %) patients with stage IV. Patients with primary tumors of the larynx and hypopharynx comprised 75.6 % of the study population, patients with recurrent tumors – 24.4 %. During diagnosis advancement of tumors to the anatomical structures in the laryngeal space and beyond was evaluated. In all cases histological verification of the diagnosis was performed. Comparison of the data on advancement of laryngeal and hypopharyngeal tumors from different diagnostic methods with the results of histological examination depending on the T-category (TNM) was performed.Results. For small tumors (Т1), frequency of agreement between advancement of laryngeal and hypopharyngeal tumors measured by US examination and histological examination was 66.7 %, by endoscopic laryngoscopy (ELS) – 80.0 %; for T2 tumors, results of US examination and ELS were identical, frequency of agreement with histological examination data was 87.2 % for both methods; for T3 tumors, US examination data agreed with histological examination data in 83.3 % of cases, ELS data – in 75.0 %; for T4 tumors, frequency of agreement between US examination and histological examination data was only 44.4 %, between ELS and histological examination – 66.7 %. Therefore, US examination was more accurate for evaluation of advancement of T2 and T3 tumors. Results of evaluation of advancement of laryngeal and hypopharyngeal tumors by US examination, computed tomography and magnetic resonance tomography were close, comparable and weren’t statistically different. For T1 and T2 tumors frequency of agreement between the results of histological examination and US examination data was higher than between the results of histological examination and computed tomography data.Conclusions. High accuracy and value of US examination in evaluation of advancement of primary and recurrent tumors of the larynx and hypopharynx were shown.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Johannes R. Kratz ◽  
Jack Z. Li ◽  
Jessica Tsui ◽  
Jen C. Lee ◽  
Vivianne W. Ding ◽  
...  

AbstractAlthough surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi46-vi46
Author(s):  
Fumi Higuchi ◽  
Takeo Uzuka ◽  
Keisuke Ueki

Abstract Oligodendrogliomas with 1p/19q-codeletion are relatively slow progressive tumors that show good response to chemo-radiation therapy after resection. The median survival is about 15 years regardless of WHO grade, although recurrences are mostly inevitable and there is no standard treatment for recurrence. We experienced 5 oligodendroglioma cases who underwent re-radiation for recurrent tumors after chemo-radiation treatment. We retrospectively investigated those for response to re-radiation, the duration from first radiation to second radiation, and Karnofsky Performance Status (KPS) before and after the re-radiation. Patients were all male; the median radiation dose for primary tumor was 60Gy (54-60Gy), the median age at first radiation was 46 years (35-59), the median duration from the first radiation to re-radiation was 65 months (range 18-116 months), and the median follow-up period after re-radiation was 15 months (1-39 months). In all 5 cases, tumors showed good response to re-radiation. In 3 of the 5 cases, tumor recurred in corpus callosum and/or lateral side of cerebral hemisphere or basal ganglia contiguous with primary tumor sites and were radiated by IMRT (50Gy/25fr) . In 2 cases, tumors recurred around the fourth ventricle and posterior fossa and underwent conventional radiation (54Gy/30fr and 30Gy/10fr). In 2 of the 5 cases, the tumors re-recurred 24 months later after re-radiation, but the KPS were maintained until re-recurrence. For oligodendrogliomas, re-radiation therapy appears to be very effective to recurrent tumors after first chemo-radiation. Although evaluation for longer-term side effects is to be examined, re-radiation appears to be a good option for recurrent oligodendrogliomas after first chemo-radiation therapy.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi101-vi101
Author(s):  
Tala Shekarian ◽  
Marie-Françoise Ritz ◽  
Tomàs Martins ◽  
Philip Schmassmann ◽  
Gregor Hutter

Abstract BACKGROUND To target tumor-induced immune evasion mechanisms of glioblastoma for clinical research, we aimed at characterizing the immunological changes in patient-matched treatment-naïve and recurrent GBM samples. MATERIAL AND METHODS Proteins and total RNA were extracted from 15 patient-matched treatment-naïve (primary) and recurrent GBM fresh frozen tumor samples. The expression of genes involved in brain immune responses were compared using Nanostring panels encompassing Cancer and Neuroinflammation genes. Correlation analysis using log2-transformed patient-matched recurrent/primary expression ratio (log2(P/R)) and clinical outcome data (time to relapse and overall survival (OS)) was conducted. Proteomic was conducted to compare total protein expressions. Moreover, immunostaining was performed on a tissue microarray of matched tumor samples to visualize CD64+ cells, CD47+ tumor cells and microglia in order to assess quantitative transcriptome of these specific cell types using GeoMX technology. Functional assays are designed for deciphering phagocytosis induction by factors produced by primary and recurrent tumors. RESULTS Genes significantly differentially expressed between primary and recurrent tumors revealed “Antigen presentation” and “Microglia Pathogen Phagocytosis” as the most significant pathways enriched in recurrent tumors. Considering individual genes, a strong negative correlation (R2>0.4) between log2(R/P) and time to relapse and OS was found for 2 genes, FCGR1A (CD64) and CD47. We observed that only CD64 expression levels in recurrent samples also negatively correlated with OS. CD64 and CD47 proteins were quantified by proteomic analysis and log2 (R/P) of their levels also negatively correlated with time to relapse. Immunostaining revealed numerous CD64-positive cells in tumor biopsies resembling bushy or amoeboid microglia. CONCLUSION Upregulation of CD64 and CD47 expressions in recurrent GBM was identified as a negative predictor for time to relapse and OS. This suggests an important role of CD64 and CD47 and related inflammation dysregulation in tumor resistance and regrowth. Interfering with CD64-induced functions may represent a novel therapeutic option for GBM.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A862-A862
Author(s):  
Zachary Sethna ◽  
Marta Luksza ◽  
Luis Rojas ◽  
Kevin Soares ◽  
Joanne Leung ◽  
...  

BackgroundCancer immunoediting predicts that T cells selectively kill tumor cells expressing immunogenic mutations (neoantigens) resulting in less immunogenic clones to outgrow in tumors.1 Although established through longitudinal studies of how tumors evolve in immune-proficient and -deficient mice,1 2 whether the human immune system naturally targets neoantigens to edit tumors, and the principles that identify the edited neoantigens, remains unclear.MethodsTo investigate if immune selective pressures on neoantigens alter how human tumors evolve, we longitudinally studied how 70 human pancreatic ductal adenocarcinomas (PDACs) - a poorly immunogenic cancer largely presumed to not be subject to immunoediting - evolved over 10 years. We use exome sequencing, neoantigen identification, and clonal reconstruction to compare how primary PDACs evolve to recurrence in rare long-term PDAC survivors previously shown to have more immunogenic tumors3 (n = 9 patients, n = 9 primary, 22 recurrent tumors), to short-term survivors with less immunogenic primary tumors (n = 6 patients, n = 6 primary, 33 recurrent tumors). To identify immunogenic “high quality” neoantigens, we use neopeptide-T cell functional assays and computational modeling to extend and apply a previously developed neoantigen quality model3 4 by predicting high quality neoantigens as arising from amino acid substitutions with sufficient antigenic distance from cognate wild-type peptides to differentially bind the MHC or activate a T cell.ResultsCompared to short-term survivors, we observe that long-term survivors evolve fewer recurrent tumors with longer latency, and distinct tissue tropism. To evaluate if differential immune pressures explained these differences, we discover that despite longer times to evolve, long-term survivors evolve genetically less heterogeneous tumors with fewer clones, fewer nonsynonymous mutations, and fewer neoantigens. To identify if high quality neoantigens are selectively edited in recurrent tumors of long-term survivors, we observe that neoantigens with greater antigenic distance (“less self”) are more depleted in primary and recurrent tumors of long- compared to short-term survivors. Furthermore, we find that long-term survivors evolve markedly fewer new neoantigens of strikingly lower quality, to indicate clones with high quality neoantigens are immunoedited.ConclusionsWe submit longitudinal evidence that the human immune system naturally edits neoantigens in PDAC. Furthermore, we present a model that describes how cancer neoantigens evolve under immune pressure over time, with implications for cancer biology and therapy. More broadly, our results argue that immunoediting is a fundamental cancer suppressive mechanism that can be quantified to predict tumor evolution.AcknowledgementsThis work was supported by NIH U01 CA224175 (V.P.B), a Stand Up to Cancer Convergence Award (B.D.G, V.P.B.), a Damon Runyon Clinical Investigator Award (V.P.B), and the Avner Pancreatic Cancer Foundation (A.J, A.G). Services by the Integrated Genomics Core were funded by the NCI Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.ReferencesShankaran V, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001;410:1107–1111.Matsushita H, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012;482:400–404.Balachandran VP, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 2017;551:512–516.Łuksza M, et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 2017;551:517–520.Ethics ApprovalThis study was performed in strict compliance with all institutional ethical regulations and approved by the institutional review boards of Memorial Sloan Kettering Cancer Center (MSK), the Garvan Institute of Medical Research, and the The Johns Hopkins Hospital (JHH). We obtained informed consent from all patients.


2021 ◽  
Vol 10 (21) ◽  
pp. 5105
Author(s):  
Ana Plata ◽  
Félix Guerrero-Ramos ◽  
Carlos Garcia ◽  
Alejandro González-Díaz ◽  
Ignacio Gonzalez-Valcárcel ◽  
...  

(1) Background: Intravesical mitomycin-C (MMC) combined with hyperthermia is increasingly used in non-muscle invasive bladder cancer (NMIBC), especially in the context of a relative BCG shortage. We aim to determine real-world data on the long-term treatment outcomes of adjunct hyperthermic intravesical chemotherapy (HIVEC) with MMC and a COMBAT® bladder recirculation system (BRS); (2) Methods: A prospective observational trial was performed on patients with NMIBC treated with HIVEC using BRS in nine academic institutions in Spain between 2012–2020 (HIVEC-E). Treatment effectiveness (recurrence, progression and overall mortality) was evaluated in patients treated with HIVEC MMC 40mg in the adjuvant setting, with baseline data and a clinical follow-up, that comprise the Full Analysis Set (FAS). Safety, according to the number and severity of adverse effects (AEs), was evaluated in the safety (SAF) population, composed by patients with at least one adjunct HIVEC MMC instillation; (3) Results: The FAS population (n = 502) received a median number of 8.78 ± 3.28 (range 1–20) HIVEC MMC instillations. The median follow-up duration was 24.5 ± 16.5 (range 1–81) months. Its distribution, based on EAU risk stratification, was 297 (59.2%) for intermediate and 205 (40.8%) for high-risk. The figures for five-year recurrence-free and progression-free survival were 50.37% (53.3% for intermediate and 47.14% for high-risk) and 89.83% (94.02% for intermediate and 84.23% for high-risk), respectively. A multivariate analysis identified recurrent tumors (HR 1.83), the duration of adjuvant HIVEC therapy <4 months (HR 1.72) and that high-risk group (HR 1.47) were at an increased risk of recurrence. Independent factors of progression were high-risk (HR 3.89), recurrent tumors (HR 3.32) and the induction of HIVEC therapy without maintenance (HR 2.37). The overall survival was determined by patient age at diagnosis (HR 3.36) and the treatment duration (HR 1.82). The SAF population (n = 592) revealed 406 (68.58%) patients without AEs and 186 (31.42%) with at least one AE: 170 (28.72%) of grade 1–2 and 16 (2.7%) of grade 3–4. The most frequent AEs were dysuria (10%), pain (7.1%), urgency (5.7%), skin rash (4.9%), spasms (3.7%) and hematuria (3.6%); (4) Conclusions: HIVEC using BRS is efficacious and well tolerated. A longer treatment duration, its use in naïve patients and the intermediate-risk disease are independent determinants of success. Furthermore, a monthly maintenance of adjunct MMC HIVEC diminishes the progression rate of NMIBC.


PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258802
Author(s):  
Mohammad Alabduljabbar ◽  
Diego Strianese ◽  
Osama Al-Sheikh ◽  
Hind M. Alkatan ◽  
Hailah Al-Hussain ◽  
...  

To evaluate and compare the clinical and histopathological profile of primary and recurrent orbital-periorbital plexiform neurofibromas (OPPN) in patients with neurofibromatosis type 1. We retrospectively evaluated 43 primary or recurrent neurofibroma (NF) specimens from 26 patients (2002 to 2018) at the King Khaled Eye Specialist Hospital, Saudi Arabia. Demographics, clinical presentation, and surgical intervention data were collected. Histopathological specimens were studied with hematoxylin-eosin, Alcian blue, and immunohistochemical markers; S-100, CD44, CD117, smooth muscle actin (SMA), neurofilament, and Ki-67. Of the 43 NFs specimens, 20 were primary and 23 recurrent tumors. For primary NF, the ratio of plexiform to the diffuse type was 13:7, however in recurrent tumors was 3:8 after the first recurrence, and 1:5 after multiple recurrences. Of the 17 patients with primary tumors that had paired recurrent tumors, 12/17 (70.6%) primary NFs were plexiform and 5/17 (29.4%) were diffuse. However, when tumors recurred, 13/17 tumors (76.5%) were diffuse and only 4/17 tumors (23.5%) had a plexiform pattern. The odds of a tumor having a diffuse pattern in recurrent NF was significantly higher than the plexiform pattern [OR = 7.8 (95% confidence interval 1.69:36.1) P = 0.008]. Primary plexiform NFs underwent an excision at a significantly younger age than the diffuse type. Recurrent NFs had significantly higher CD44, CD117, and neurofilament labeling (P = 0.02, P = 0.01 and P<0.001 respectively) but had significantly decreased Alcian blue, and S-100 labeling (P = 0.03, and P = 0.02 respectively) compared to primary tumors. SMA and Ki-67 proliferation index were not different between primary and recurrent NFs (P = 0.86, and P = 0.3 respectively). There appears to be a high risk for primary plexiform NFs to develop a diffuse histologic pattern when they recur. Immunohistochemical staining suggests a role of mast cells (CD117) and expression of infiltration makers (CD44) in the transformation of plexiform tumors to the diffuse phenotype.


2021 ◽  
Vol 43 (2) ◽  
pp. 28-31
Author(s):  
M. I. Goldstein

The decisive method for the treatment of malignant neoplasms of the stomach is surgical intervention. The successes achieved in this direction are limited mainly to surgery for primary cancer of the stomach. Patients with recurrent tumors in the stomach stump, as well as with secondary malignant neoplasms in this area after surgery for peptic ulcer, polyps and other diseases, were considered doomed and hopeless until recently.


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