IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology

2021 ◽  
Vol 80 (3) ◽  
pp. 247-253
Author(s):  
Yohei Miyake ◽  
Keita Fujii ◽  
Taishi Nakamaura ◽  
Naoki Ikegaya ◽  
Yuko Matsushita ◽  
...  

Abstract Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13504-e13504 ◽  
Author(s):  
Timothy Francis Cloughesy ◽  
Derek Ostertag ◽  
Joseph C. Landolfi ◽  
Tobias Walbert ◽  
Michael A. Vogelbaum ◽  
...  

e13504 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to cell division requirements for virus integration into the genome and defects in innate and adaptive immune responses found in cancers that support virus replication. Toca 511 spreads through cancer cells and stably delivers the gene for an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil (5-FU). 5-FU kills infected cancer cells that are dividing, diffuses and kills surrounding cancer cells as well as myeloid derived suppressor cells and tumor associated macrophages, thus reestablishing immunity to tumor. Methods: In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with recurrent high grade glioma undergoing resection, followed by oral administration of courses of Toca FC 5-7 weeks after Toca 511 injection. Additional cohorts included combination of Toca 511 & Toca FC with bevacizumab or lomustine. Results: Objective responses (ORs) are observed in IDH1 wildtype (wt) and mutant (mt) phenotypes, including 3 complete responses (CRs) (2 IDH1 mt and 1 IDH1 wt) and 2 partial responses (2 IDH1 wt) for patients treated with Toca 511 & Toca FC, and 1 CR (1 IDH1 mt) for a patient treated with Toca 511 & Toca FC and bevacizumab. ORs are observed 6-19 months after Toca 511 injection and are consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDOR) is 25.2 months. Excluding the combination cohorts, mDOR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of OR and OS. An additional radiologic CR is observed in 1 IDH1 mt patient at 1st recurrence who received intravenous Toca 511 plus injection into the resection bed. All 4 IDH1 mt patients treated at 1st recurrence had CRs. Conclusions: There may be an association between ORs and IDH1 mutation with Toca 511 & Toca FC treatment. Updated clinical benefit, molecular profiles and tumor mutational load are reported. Clinical trial information: NCT01470794.


2015 ◽  
Vol 112 (35) ◽  
pp. 10995-11000 ◽  
Author(s):  
J. Zachary Sanborn ◽  
Jongsuk Chung ◽  
Elizabeth Purdom ◽  
Nicholas J. Wang ◽  
Hojabr Kakavand ◽  
...  

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.


2020 ◽  
Author(s):  
Liwei Yang ◽  
Jing Yan Zhu ◽  
Yihe Zhang ◽  
Wenjie Zhou ◽  
Yicheng Si

Abstract Commercial flights contributed to the early-stage international transmission of SARS-CoV-2. Understanding the effect of international and inter-state flights on virus transmission is important to evaluate the initial response of the outbreak. This study investigated the likely date of the emergence of the first COVID-19 case. We constructed a geographical-structured epidemiology model, integrating 2541 province-level units, 250 country-level units, and 26,094,036 flight plans to evaluate the possible date of the emergence of the first case. Using the model, we estimated the number of cumulative deaths and the date of first death caused by COVID-19 in different countries. The pattern of the three parameters we evaluated suggests a high likelihood of the emergence of the first case of COVID-19 be around September 15 and September 22, 2019.


2021 ◽  
Vol 12 ◽  
Author(s):  
Mahmoud S. Alghamri ◽  
Brandon L. McClellan ◽  
Margaret S. Hartlage ◽  
Santiago Haase ◽  
Syed Mohd Faisal ◽  
...  

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15  months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zaoqu Liu ◽  
Taoyuan Lu ◽  
Libo Wang ◽  
Long Liu ◽  
Lifeng Li ◽  
...  

Background: Glioma is the most common malignant brain tumor with complex carcinogenic process and poor prognosis. The current molecular classification cannot fully elucidate the molecular diversity of glioma.Methods: Using broad public datasets, we performed cluster analysis based on the mutational signatures and further investigated the multidimensional heterogeneity of the novel glioma molecular subtypes. The clinical significance and immune landscape of four clusters also investigated. The nomogram was developed using the mutational clusters and clinical characteristics.Results: Four heterogenous clusters were identified, termed C1, C2, C3, and C4, respectively. These clusters presented distinct molecular features: C1 was characterized by signature 1, PTEN mutation, chromosome seven amplification and chromosome 10 deletion; C2 was characterized by signature 8 and FLG mutation; C3 was characterized by signature 3 and 13, ATRX and TP53 mutations, and 11p15.1, 11p15.5, and 13q14.2 deletions; and C4 was characterized by signature 16, IDH1 mutation and chromosome 1p and 19q deletions. These clusters also varied in biological functions and immune status. We underlined the potential immune escape mechanisms: abundant stromal and immunosuppressive cells infiltration and immune checkpoints (ICPs) blockade in C1; lack of immune cells, low immunogenicity and antigen presentation defect in C2 and C4; and ICPs blockade in C3. Moreover, C4 possessed a better prognosis, and C1 and C3 were more likely to benefit from immunotherapy. A nomogram with excellent performance was also developed for assessing the prognosis of patients with glioma.Conclusion: Our results can enhance the mastery of molecular features and facilitate the precise treatment and clinical management of glioma.


2018 ◽  
Vol 36 (6) ◽  
pp. 470-478
Author(s):  
Rüdiger Braun ◽  
Hans-Peter Bruch ◽  
Tobias Keck ◽  
Claudia Benecke ◽  
Martin Hoffmann

Background: Despite multimodal treatment strategies, locoregional recurrence rates are still significant in colorectal carcinoma (CRC). Methods: Clinical, pathological, perioperative, and survival data of 203 patients with recurrent CRC enlisted in a prospective database from 1990 to 2011 were analyzed. Results: Median disease-free survival in our cohort of 203 patients was 23 months after resection of the primary tumor. In total, 113 of these patients had surgical therapy with resection of the recurrent tumor. The primary tumor was localized in the rectum in 63 (56%) patients and in the colon in 50 (44%) patients. A complete resection of the recurrent tumor (R0) was achieved in 69 (61%) patients. Postoperative complications occurred in 42 (37%) patients. Postoperative mortality was 2.7%. The median overall survival for R0-resected patients without distant metastasis was 91 months. Those patients had better overall survival compared to patients in whom no complete resection of the recurrent tumor was possible (p < 0.001). There was no statistically significant difference (overall survival) between patients that had R0-resection with systemic metastasis and R1 (p = 0.794) or R2 (p = 0.422) resection. Conclusion: Surgical resection of a locally recurrent CRC leads to a substantial long-term survival rate for R0-resected patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Pietro Parcesepe ◽  
Luigi Coppola ◽  
Andrea Remo ◽  
Mario Rosario D’Andrea ◽  
Giulia Coppola ◽  
...  

Malignant Brenner Tumor (mBT) is extremely rare. Although BT are almost exclusive ovarian neoplasms, they may constitute a highly unusual tumor of the testis; in fact, only seven fully documented cases have been reported to date. Because of their rarity, the pathogenesis of these tumors has not been clarified and there is no standard therapeutic approach. We report the first case of epididymal mBT with synchronous, multiple, liver metastases and a very dramatic clinical course. Both primary tumor and metastasis were subjected to mutational analysis of 20 cancer associated genes. Primary tumor showed FGFR3 Tyr375Cys and PIK3CA His1047Arg missense mutations. Both mutations are reported as pathogenic in ClinVar database. The same FGFR3 mutation was present in liver metastasis. Based on these results we believe that the FGFR pathway could be an ideal candidate for personalized treatment, offering hope to a subset of patients with mBT. Personalized approach, including mutational analysis and molecular testing should be required in patients with rare tumors in order to clarify diagnosis and improve therapeutic strategies.


2021 ◽  
pp. 20210015
Author(s):  
Rosy Setiawati ◽  
Eveline Stephanie Lay ◽  
Valentina Testini ◽  
Paulus Rahardjo ◽  
Mouli Edward ◽  
...  

Objective: Synchronous multifocal osteosarcoma is a rare condition in which the osteosarcoma presents with multiple bone lesions at the time of diagnosis, usually without any visceral metastases. The first case was described in early 1930s by Silverman. To report a case of synchronous multifocal osteosarcoma in adolescent with pathologic fracture. Methods: An 18-year-old girl presented with a painful mass in the right thigh of 4 months’ duration and a history of thigh bone fracture a month ago. Patient’s medical records and family history was unremarkable. Physical examination showed angulation and shortening at right femoral region with tenderness and swelling. Initial radiograph and magnetic resonance (MR) images showed multiple lesions in right femoral shaft and pelvic bone with primary tumor in right distal femur with pathologic fracture and multiple bone marrow lesions found in the contralateral bones. Imaging and histopathologic results supported the diagnosis of synchronous multifocal osteosarcoma. After following the chemotherapy as the treatment of choice, the radiograph and MRI evaluation were done and showed reduction of the mass size with union of the destructed part with the formation of callus. The advance MRI revealed reduction of the overall mass and the composition of the viable area compared to previous study. The patient had satisfying response to chemotherapy series and a better functional outcome on subsequent visits. Results: Diagnosis of synchronous multifocal osteosarcoma was based on patient and family history and finding of multiple lesions in the MR images, meanwhile the plain radiograph only revealed the primary tumor. Amstutz described multifocal osteosarcoma as presence of one primary tumor and several smaller lesions. Most recent reviews concluded that multifocal osteosarcoma is bone-to-bone metastatic process rather than multicentric origin. The limitation in this case was absence of thoracic CT which is suggested to rule out any pulmonary metastases instead of routine chest radiograph. Conclusions: Although satisfying improvement was clinically achieved, further advanced MRI would be indicated to evaluate the progression of tumor and its respond to therapy.


2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
C Oliveira Da Silva ◽  
S Eliasson ◽  
C Sequeira ◽  
A Bernardes ◽  
E Gunyeli ◽  
...  

Abstract Introduction Chloroma, also known as myeloid sarcoma, is a localized extramedullary tumour composed of malignant cells of the myeloid cell line, most frequently occurring in myelogenous leukemia. Heart involvement is exceptional, only about 20 cases have been reported in the literature. Case presentation A 38-year-old woman presenting with fatigue and pre-syncope was admitted to the hospital. The patient had a history of acute myeloid leukaemia diagnosed 2017, treated with chemotherapy and transplanted with allogenic bone-marrow the same year, remaining thereafter in clinical remission. Initial electrocardiogram showed sinus bradycardia and recurrent sinus arrests and therefore a pacemaker was implanted. An echocardiogram was performed which revealed multiple infiltrative masses with involvement of the superior vena cava extending to the right atrium, atrial septum, left atrium, mitral valve and aortic root. Magnetic resonance imaging was done confirming the echocardiographic results and showing even involvement of pulmonary veins, coronary arteries and myocardial infiltration. Chemoradiation was administered with initial response, however, disease progression led to the patients´death. Conclusion To our knowledge, this is the first case describing a chloroma with extensive involvement of cardiac walls, vessels and valves. This case also illustrates the value of echocardiography as a tool for early detection of cardiac masses. Abstract 473 Figure. Echo with contrast


2020 ◽  
Author(s):  
Ben B. Hui ◽  
Damien Brown ◽  
Rebecca H. Chisholm ◽  
Nicholas Geard ◽  
Jodie McVernon ◽  
...  

AbstractBackgroundRemote Australian Aboriginal and Torres Strait Islander communities have potential to be severely impacted by COVID-19, with multiple factors predisposing to increased transmission and disease severity. Our modelling aims to inform optimal public health responses.MethodsAn individual-based simulation model represented communities ranging from 100 to 3,500 people, comprised of large interconnected households. A range of strategies for case finding, quarantining of contacts, testing, and lockdown were examined, following the silent introduction of a case.ResultsMultiple secondary infections are likely present by the time the first case is identified. Quarantine of close contacts, defined by extended household membership, can reduce peak infection prevalence from 60-70% to around 10%, but subsequent waves may occur when community mixing resumes. Exit testing significantly reduces ongoing transmission.Concurrent lockdown of non-quarantined households for 14 days is highly effective for epidemic control and reduces overall testing requirements; peak prevalence of the initial outbreak can be constrained to less than 5%, and the final community attack rate to less than 10% in modelled scenarios. Lockdown also mitigates the effect of a delay in the initial response. Compliance with lockdown must be at least 80-90%, however, or epidemic control will be lost.ConclusionsA SARS-CoV-2 outbreak will spread rapidly in remote communities. Prompt case detection with quarantining of extended-household contacts and a 14-day lockdown for all other residents, combined with exit testing for all, is the most effective strategy for rapid containment. Compliance is crucial, underscoring the need for community supported, culturally sensitive responses.


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