scholarly journals Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 47
Author(s):  
Cristina Birzu ◽  
Pim French ◽  
Mario Caccese ◽  
Giulia Cerretti ◽  
Ahmed Idbaih ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Recurrent Glioblastoma ◽  
Molecular Characteristics ◽  
Specific Gene ◽  
Primary Tumors ◽  
First Line Therapy

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals Systemic treatment options for advanced biliary tract carcinoma

2020 ◽  
Vol 55 (10) ◽  
pp. 944-957
Author(s):  
Changqing Xie ◽  
Nicole A. McGrath ◽  
Cecilia Monge Bonilla ◽  
Jianyang Fu
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Biliary Tract ◽  
Treatment Options ◽  
Single Agent ◽  
Current Status ◽  
Dna Mismatch ◽  
First Line Therapy ◽  
Molecular Landscape ◽  
Line Setting

Abstract Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.

scholarly journals Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1404-1411 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Efstathios Kastritis ◽  
Roger G. Owen ◽  
Robert A. Kyle ◽  
Ola Landgren ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Autologous Transplantation ◽  
Mammalian Target Of Rapamycin ◽  
Proteasome Inhibitors ◽  
Young Patients ◽  
Treatment Recommendations ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia

Abstract Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

scholarly journals Integrative Concepts for Liver Surgery

2020 ◽  
Vol 36 (5) ◽  
pp. 351-358
Author(s):  
Stefan Heinrich ◽  
Felix Watzka ◽  
Hauke Lang
Keyword(s):  
Liver Transplantation ◽  
Patient Selection ◽  
Liver Surgery ◽  
Liver Tumors ◽  
Treatment Options ◽  
Molecular Characteristics ◽  
Primary Tumors ◽  
Primary Liver Tumors ◽  
Liver Resections ◽  
Systemic Treatments

<b><i>Background:</i></b> Surgery is the standard treatment for primary tumors and metastases. Due to improvements in surgical outcomes as well as the efficacy of systemic treatments, the role of surgery has changed in recent years. <b><i>Summary:</i></b> Liver surgery has become safe and efficient, with resectability being increased by multimodality concepts as well as staged liver resections and orthotopic liver transplantation. These concepts may be applied to primary liver tumors but also to selected patients with liver metastases from various diseases. In addition, even debulking surgery may be indicated for selected patients with endocrine metastases. While patient selection for liver resections was limited to clinical parameters in the past, histological and molecular characteristics have become increasingly important. Moreover, the response to regional or systemic chemotherapy has been demonstrated to be strong for a beneficial course of the disease even in advanced diseases. <b><i>Key-Messages:</i></b> Due to the variety of available treatment options, optimal patient selection is crucial. Besides liver surgery, staged concepts as well as liver transplantation are curative tools for many patients.

scholarly journals Recent advances in the management of anaplastic thyroid cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Simone De Leo ◽  
Matteo Trevisan ◽  
Laura Fugazzola
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Anaplastic Thyroid Cancer ◽  
Genetic Alterations ◽  
Genetic Profile ◽  
Mutational Status ◽  
Single Target

AbstractAnaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAFV600E mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAFV600E mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.

Sunitinib dosing, toxicity, and outcomes in first-line advanced renal cell carcinoma (aRCC): A U.S. Oncology Network (USON) retrospective study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15089-e15089
Author(s):  
Ian D. Schnadig ◽  
Thomas E. Hutson ◽  
Hsingwen Chung ◽  
Rahul Dhanda ◽  
Melissa Halm ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Retrospective Study ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Median Number ◽  
First Line ◽  
Primary Tumors ◽  
Full Dose ◽  
First Line Therapy ◽  
Dose Reductions

e15089 Background: Sunitinib is a first-line therapy for patients (pts) with aRCC. As a multitargeted tyrosine kinase inhibitor (TKI), it is associated with toxicities that may impact dosing; dose reductions may result in inferior clinical outcomes (Motzer, 2011 ASCO GU, abstract LBA308). This retrospective study was initiated by USON to evaluate dosing patterns of first-line sunitinib, and its association with toxicities and outcomes in community practices. Methods: Pts with aRCC who started first-line sunitinib between June 1, 2007 and May 31, 2011 at 17 USON practices were identified; clinical data were extracted by chart review from iKnowMed electronic medical records that were linked to USON retail pharmacy database. Pts who were enrolled in clinical trials or receiving care for other primary tumors were excluded. Results: Pt characteristics: N=134; median age = 64 years (range 41–87); ECOG PS 0/1 = 85%; clear cell RCC = 81%; and nephrectomy = 61%. Objective response rate was 16%. Overall survival (OS) was 15.4 months (95% confidence interval 11.9–20.8). Median treatment duration was 4 cycles (range 1–19): 27 pts (20.1%) received only 1 cycle of sunitinib (23 at full dose [50 mg] and 4 at <full dose); 107 pts (79.9%) received >1 cycle of sunitinib (53 received full dose; 35 started at full dose but were dose-reduced; 14 always received <full dose; 5 started at <full dose but were dose-increased to 50 mg). Overall, 45 pts were dose-reduced, principally (93%) due to toxicities; 67% of all dose reductions occurred in the first 3 cycles. 121 pts discontinued sunitinib after completing at least 1 cycle, mostly due to disease progression (PD; 44%) or toxicities (17%); 74% of all discontinuations occurred within the first 5 cycles. Conclusions: RCC pts in community practices commonly undergo sunitinib dose reductions in the first 3 cycles due to toxicities, and discontinue therapy within the first 5 cycles due to PD. The median number of cycles and OS were lower than those reported in clinical trials (Motzer JCO 2009;27:3584–3590). More selective TKIs are needed to reduce toxicities, optimize dosing, and potentially improve outcomes. Funded by a grant from AVEO Pharmaceuticals, Inc.

scholarly journals Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5022
Author(s):  
Cristina Riobello ◽  
Paula Sánchez-Fernández ◽  
Virginia N. Cabal ◽  
Rocío García-Marín ◽  
Laura Suárez-Fernández ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Wide Spectrum ◽  
Tumor Development ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Activity Level ◽  
Intestinal Type ◽  
Specific Gene ◽  
Intestinal Type Adenocarcinoma

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.

scholarly journals A comprehensive study on the oncogenic mutation and molecular pathology in Chinese lung adenocarcinoma patients

2020 ◽  
Author(s):  
Xilin Zhang ◽  
Yan Jiang ◽  
Huanming Yu ◽  
Hui Xia ◽  
Xiang Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Critical Role ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Molecular Characteristics ◽  
Novel Therapy ◽  
Multiple Gene ◽  
Oncogenic Mutation ◽  
Therapy Strategy

Abstract Background: Several driver genetic alterations have been identified in micropapillary lung adenocarcinoma (MPA). However, the frequency of ROS1 rearrangements is yet unclear. Herein, we investigated the associations between clinicopathological and molecular characteristics of MPA compared with non-micropapillary lung adenocarcinoma (LA).Methods: FFPE sections derived from lung adenocarcinoma patients who never received adjuvant chemotherapy or radiation therapy prior to surgical resection were collected from October 2016 to June 2019. EGFR mutations, ROS1 rearrangements and EML4-ALK fusions were identified in a set of 131 MPA and LA cases by using the Amplification Refractory Mutation System.Results: EGFR mutations had occurred in 42 (76.4%) MPA patients and 42 (55.3%) LA patients. But interestingly, ROS1 rearrangement was present in 10.9% (6/55) MPA cases and 1.3% (1/76) LA cases. Moreover, 7.3% (4/55) MPA samples had multiple gene mutations, while only 1.3% (1/76) LA cases had double gene alterations.Conclusions: A higher prevalence of ROS1 rearrangements or combined mutations of ROS1 and EGFR or EML4-ALK may play a critical role in the tumorigenesis of MPA. These finding provides a novel therapy strategy for the patients with malignant MPA through combining TKIs than one TKI.

scholarly journals Recent drug approvals for acute myeloid leukemia

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Catherine Lai ◽  
Kimberley Doucette ◽  
Kelly Norsworthy
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Gene Mutations ◽  
Review Article ◽  
New Drugs ◽  
Specific Gene ◽  
New Agents ◽  
Survival Pathways ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age, and a generally poor prognosis. The disease is clinically and genetically heterogeneous, and recent advances have improved our understanding of the cytogenetic abnormalities and molecular mutations, aiding in prognostication and risk stratification. Until recently, however, therapeutic options were mostly limited to cytotoxic chemotherapy. Since 2017, there has been an explosion of newly approved treatment options both nationally and internationally, with the majority of new drugs targeting specific gene mutations and/or pivotal cell survival pathways. In this review article, we will discuss these new agents approved for the treatment of AML within the last 2 years, and will outline the mechanistic features and clinical trials that led to their approvals.

scholarly journals A rare case of myelodysplastic syndrome with refractory thrombocytopenia

2015 ◽  
Vol 7 (3) ◽  
Author(s):  
Waqas Jehangir ◽  
John Webb ◽  
Shilpi Singh ◽  
Sabrina Arshed ◽  
Shuvendu Sen ◽  
...  
Keyword(s):  
Rare Case ◽  
Treatment Options ◽  
Gene Mutations ◽  
Mortality Rates ◽  
Morbidity And Mortality ◽  
Genetic Mutations ◽  
Specific Gene ◽  
High Morbidity ◽  
Risk Patients ◽  
Evidenced Based

Myelodysplastic syndromes (MDS) represent a variety of clonal abnormalities, possibly preleukemic and display numerous phenotypic manifestations. Specific mutations carry high morbidity and mortality rates due to cell line dysplasia. MDS commonly presents with symptoms related to anemia, and approximately two-thirds will develop thrombocytopenia, a rare, but potentially lethal complication that increases complexity in treatment and morbidity, and may be due to unique genetic mutations leading to refractory thrombocytopenia, ultimately leading to an overall reduction in survival. Careful identification and monitoring of this patient subdivision can significantly reduce morbidity and mortality, and potential identification of specific gene mutations and advances in treatment options will hopefully provide guidance on detecting at-risk patients in the future. We present a case of a man with MDS-U (karyotype 46, XY, del (20) (q11.2q13.3) (20) with no detected <em>JAK2</em> <em>V617F</em> mutation), who in despite of appropriate evidenced based treatment, continued to exhibit refractory thrombocytopenia.

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