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2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Vanessa F. Bonazzi ◽  
Olga Kondrashova ◽  
Deborah Smith ◽  
Katia Nones ◽  
Asmerom T. Sengal ◽  
...  

Abstract Background Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. Results PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature. Conclusions EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.


2022 ◽  
Vol 6 (3) ◽  
pp. 1423-1434
Author(s):  
Denny Satria Utama ◽  
Eriza ◽  
Priscilla Ralahayu ◽  
Erial Bahar

Background. Nasopharyngeal carcinoma is a malignant tumor that grows in the nasopharyngeal area with predilection in the fossa Rossenmuller and the nasopharyngeal roof adjacent to the Eustachian tube, so one of NPC’s early symptoms is ear symptoms. Hearing loss is a common symptom found in people with NPC due to dysfunction of the Eustachian tube, a continuing middle ear disorder that can result in conductive hearing loss.This study aims to find out the relationship between primary tumor of NPC and the degree of conductive hearing loss at dr. Mohammad Hoesin Hospital Palembang. Methods. This is a cross sectional study that obtained 42 samples from the medical records at Dr. Mohammad Hoesin Hospital Palembang that met the inclusion and exclusion criteria. The study subjects collected in total sampling have been conducted audiometry examinations at the ORLHNS clinic of Dr. Mohammad Hoesin Hospital Palembang during the period January 2019 - April 2021. Results. The proportion of hearing loss in NPC patients in this study was 30 subjects (71.4%) with the highest proportion of hearing loss complaints being 33.3%. The proportion of conductive hearing loss of nasopharyngeal carcinoma patients in the study was 33 subjects (78.5%) right ear and 28 subjects (66.7%) left ear. There was a significant association between the degree of the NPC primary tumor and the incidence of conductive deafness of the left ear, but there was no significant association in the right ear. There is a significant correlation between NPC primary tumors and left ear hearing thresholds at frequencies of 500 Hz and 4000 Hz, but there is no significant association between the degree of NPC primary tumor and right ear hearing loss. Conclusions. There is significant correlation between the primary tumor of NPC and the hearing threshold of the left ear but there was no significant association in the right ear.


Kidney Cancer ◽  
2021 ◽  
pp. 1-7
Author(s):  
Hannah Bell ◽  
Brittney H. Cotta ◽  
Simpa S. Salami ◽  
Hyung Kim ◽  
Ulka Vaishampayan

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improved OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.


2021 ◽  
Author(s):  
Hui Tang ◽  
Yingyi Wang ◽  
Chunmei Bai

Abstract Background: Lepidic adenocarcinoma (LPA) is an infrequent subtype of invasive pulmonary adenocarcinoma (ADC). However, the clinicopathological features and prognostic factors of LPA have not been elucidated.Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database of 4087 LPA patients were retrospectively analyzed and compared with non-LPA pulmonary ADC to explore the clinicopathological and prognosis features of LPA. Univariate and multivariate Cox proportional hazard models were performed to identify independent survival predictors for further nomogram development. The nomograms were validated by using the concordance index, receiver operating characteristic curves, and calibration plots, as well as decision curve analysis, in both the training and validation cohorts.Results: Compared with non-LPA pulmonary ADC patients, those with LPA exhibited unique clinicopathological features, including more elderly and female patients, smaller tumor size, less pleural invasion, and lower histological grade and stage. Multivariate analyses showed that age, sex, marital status, primary tumor size, pleural invasion, histological grade, stage, primary tumor surgery, and chemotherapy were independently associated with overall survival (OS) and cancer-specific survival (CSS) in patients with LPA, while race was the only independent prognostic factor for OS, not for CSS. The nomograms showed good accuracy compared with the actual observed results and demonstrated improved prognostic capacity compared with TNM stage.Conclusions: Patients with LPA are more likely to be older and female. Smaller tumor size, lower histological grade and stage are the clinicopathological features of LPA, which may indicate a good prognosis. The constructed nomograms accurately predict the long-term survival of LPA patients.


2021 ◽  
Vol 67 (6) ◽  
pp. 791-796
Author(s):  
Irina Akulova ◽  
Sergei Novikov ◽  
Zhanna Briantseva ◽  
Petr Krivorotko ◽  
Sergei Kanaev

          Purpose: optimization of the technique of additional irradiation of the removed tumor bed using high-dose brachytherapy for breast cancer.        Material and Methods: the results of treatment of 28 patients diagnosed with breast cancer were analyzed. After surgical treatment and a course of external radiation therapy, all patients underwent additional irradiation of the removed tumor bed using high-dose brachytherapy. The assessment of the operation protocols, the data of the pathomorphological conclusion was carried out, and on the basis of pre- and postoperative CT images, the formation of irradiation fields for high-dose brachytherapy was carried out.        Results: After deformable (nonrigid) registration of pre- and postoperative CT images of 28 patients, it was revealed that in 18 women (64.3% of cases) the location of interstitial markers and the primary tumor focus does not match topographically, which can cause incorrect formation of borders irradiation. In 35.7% of cases, radiopaque markers were located on the chest wall (on the pectoralis major muscle) when the primary tumor was located in the breast tissue. In 25% of cases, the markers were located cranial or caudal to the topography of the primary tumor focus. Label migration occurred in 3.6% of cases. In 35.7% of cases, the topography of the primary tumor node and marks completely coincided.        Conclusions: The use of deformable (non-rigid) registration of pre- and postoperative CT images is a simpler method to determine the topography of the removed tumor bed, which subsequently leads to a more accurate formation of the clinical volume of irradiation.


Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 164
Author(s):  
Shin-Cheh Chen ◽  
Shih-Che Shen ◽  
Chi-Chang Yu ◽  
Ting-Shuo Huang ◽  
Yung-Feng Lo ◽  
...  

We retrospectively enrolled 139 patients who developed metachronous isolated supraclavicular lymph node metastasis (miSLNM) from 8129 consecutive patients who underwent primary surgery between 1990 and 2008 at a single medical center. The median age was 47 years. The median follow-up time from date of primary tumor surgery was 73.1 months, and the median time to the date of neck relapse was 43.9 months in this study. Sixty-one (43.9%) patients underwent selective neck dissection (SND). The 5-year distant metastasis-free survival (DMFS), post-recurrence survival, and overall survival (OS) rates in the SND group were 31.1%, 40.3%, and 68.9%, respectively, whereas those of the no-SND group were 9.7%, 32.9%, and 57.7%, respectively (p = 0.001). No SND and time interval from primary tumor surgery to neck relapse ≤24 months were the only significant risk factors in the multivariate analysis of DMFS (hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23–2.56; p = 0.002 and HR, 1.76, 95% CI, 1.23–2.52; p = 0.002, respectively) and OS (HR, 1.77; 95% CI, 1.22–2.55; p = 0.003 and HR, 3.54, 95% CI, 2.44–5.16; p < 0.0001, respectively). Multimodal therapy, including neck dissection, significantly improved the DMFS and OS of miSLNM. Survival improvement after miSLNM control by intensive surgical treatment suggests that miSLNM is not distant metastasis. 


Author(s):  
J. Kannan ◽  
Amit Saklani ◽  
Srigopal Mohanty ◽  
Kiranmayee Narapaneni ◽  
Deepak George ◽  
...  

Background: Metastatic cervical cancer carries poor prognosis. The factors associated with distant metastasis in newly diagnosed cervical cancer patients are not clear.Methods: A retrospective analytical study was performed to study the pattern of distant metastasis, and to evaluate the factors associated with de-novo metastatic cervical cancer. Univariate and multivariate analysis (by MANOVA) were used to evaluate the association. P≤0.05 was considered significant.Results: Out of 1321 newly diagnosed cervical cancer patients, 54 (4.1%) had de-novo metastatic disease and most of which (81%) were found at single site. Common sites of distant metastasis were non-regional nodes, followed by liver, lung, peritoneum and bone. Univariate analysis showed the factors associated with de-novo metastasis were non squamous subtype, high grade histology, bulky primary tumor (>4 cm), pelvic/para-aortic lymphadenopathy, and hydroureteronephrosis. Multivariate analysis revealed the factors associated with de-novo metastasis were bulky primary tumor (>4 cm), high grade histology, pelvic/para aortic lymphadenopathy, hydroureteronephrosis.Conclusions: Newly diagnosed cervical cancer patients with bulky primary tumor, high grade histology, pelvic or para aortic lymphadenopathy, hydroureteronephrosis are associated with higher risk of de-novo distant metastasis.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Yasuyuki Takamizawa ◽  
Dai Shida ◽  
Tomoko Horie ◽  
Tsukamoto ◽  
Minoru Esaki ◽  
...  

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 18
Author(s):  
Miki Ohira ◽  
Yohko Nakamura ◽  
Tetsuya Takimoto ◽  
Atsuko Nakazawa ◽  
Tomoro Hishiki ◽  
...  

Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic and genomic markers in a Japanese NB cohort using a retrospective analysis. Follow-up data based on 30 common INRG queries in 605 NB cases diagnosed in Japan between 1990 and 2014 were collected and the genome signature of each tumor sample was integrated. As previously indicated, age, tumor stage, MYCN, DNA ploidy, the adrenals as the primary tumor site, serum ferritin and lactate dehydrogenase (LDH) levels, segmental chromosome aberrations, and the number of chromosome breakpoints (BP) correlated with lower survival rates, while the thorax as the primary tumor site and numerical chromosome aberrations correlated with a favorable prognosis. In the patient group with stage 4, MYCN non-amplified tumors (n = 225), one of the challenging subsets for risk stratification, age ≥ 18 months, LDH ≥ 1400 U/L, and BP ≥ 7 correlated with lower overall and event-free survival rates (p < 0.05). The genome subgroup GG-P2s (partial chromosome gain/loss type with 1p/11q losses and 17q gain, n = 30) was strongly associated with a lower overall survival rate (5-year survival rate: 34%, p < 0.05). Therefore, the combination of the tumor genomic pattern (GG-P2s and BP ≥ 7) with age at diagnosis and LDH will be a promising predictor for MYCN-non-amplified high-risk NBs in patient subsets, in accordance with previous findings from the INRG project.


2021 ◽  
Vol 9 (1) ◽  
pp. 25
Author(s):  
J. Kannan ◽  
Deepak George ◽  
Srigopal Mohanty ◽  
N. Ingersal ◽  
Amit Saklani

Background: Colorectal cancer (CRC) is a common cancer worldwide with significant geographical variation in its incidence. CRC among young adults is not well reported in Indian patients.Methods: A retrospective study was performed to determine the burden and to analyze the clinicopathological characteristics of newly diagnosed CRC among younger adults (<50 years). Chi-square method was used to analyze the clinicopathological characteristics. P≤0.05 was considered statistically significant.Results: CRC among younger adults comprised 40.3% of total patients median age of 40 years at diagnosis, was associated with predominantly male patients with male: female ratio of 1.8:1, positive family history, lesser co-morbidities (p=0.000), majority left sided primary tumor with left: right ratio of 4.6:1, more frequent high grade histology compared to older age group (p=0.000), advanced primary tumor and nodal metastasis. Approximately one third patients had distant metastasis at diagnosis compared to in one fourth patients in older patients. Peritoneal metastasis was significantly higher among younger adults compared to older patients (p=0.000). Significantly greater proportion of patients among younger adults initially presented with bowel obstruction (p=0.034), for which upfront emergency surgical procedures was performed in significantly higher proportion of patients compared to the older age group (p=0.007).Conclusions: Advanced stage and aggressive disease biology of CRC in younger adult warrants inclusion of one decade younger age group into present screening recommendation. 


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