Locoregional event or dyssynchronous distant metastasis: clinicopathological and molecular analysis of contralateral axillary lymph node metastasis in breast cancer patients.

AIMS: Contralateral axillary lymph node metastasis (CAM) is a rare clinical condition in patients with breast cancer (BC). CAM can be either a locoregional event or a distant metastasis. Molecular application for clonal evolution in BC has not been reported in CAM cases. METHODS: We studied six patients with CAM with clinical, pathological and/or molecular evidence of distant metastasis; those patients had poor outcomes. RESULTS: Two cases with molecular analysis of paired primary and CAM established clonal evolution of the CAM with its corresponding primary with additional molecular alteration, increased tumour mutation burden, and copy number variations (CNVs) in the CAMs. Four cases containing alterations from genes potentially modulate chromatin organization, supporting chromatin and subsequent transcriptional signature changes are essential in CAM. Molecular analysis is critical to establish the connection between CAM and its primary counterpart. Distant CAM shows clonal evolution compared with its corresponding primary with additional molecular alterations, increased mutation burden and/or copy number variations. CONCLUSION: CAM should be evaluated individually and handled in a personalized fashion. Evidence of a true metastatic CAM can be supported by distant metastasis to other organs, specific morphological features and/or clonal evolution.

Landscape of targeted therapies for advanced urothelial carcinoma.

Bladder cancer (BC) is the tenth most common malignancy globally. Urothelial carcinoma (UC) is a major type of BC, and advanced UC (aUC) is associated with poor clinical outcomes and limited survival rates. Current options for aUC treatment mainly include chemotherapy and immunotherapy. These options have moderate efficacy and modest impact on overall survival and thus highlight the need for novel therapeutic approaches. aUC patients harbor a high tumor mutation burden and abundant molecular alterations, which are the basis for targeted therapies. Erdafitinib is currently the only Food and Drug Administration (FDA)-approved targeted therapy for aUC. Many potential targeted therapeutics aiming at other molecular alterations are under investigation. This review summarizes the current understanding of molecular alterations associated with aUC targeted therapy. It also comprehensively discusses the related interventions for treatment in clinical research and the potential of using novel targeted drugs in combination therapy.

Prolonged complete response to adjuvant tepotinib in a patient with newly diagnosed disseminated glioblastoma harboring mesenchymal-epithelial transition fusion.

The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.

Molecularly matched targeted therapy: a promising approach for refractory metastatic melanoma.

BACKGROUND: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported. MATERIALS AND METHODS: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. RESULTS: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations. CONCLUSIONS: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.

Characterizing PALB2 intragenic duplication breakpoints in a triple-negative breast cancer case using long-read sequencing.

Introduction: Accurate identification and characterization of Large Genomic Rearrangements (LGR), especially duplications, are crucial for precise diagnosis and risk assessment. In this report, we characterized an intragenic duplication breakpoint of PALB2 to determine its pathogenicity significance. Methods: A 52-year-old female with triple-negative breast cancer was diagnosed with a novel PALB2 LGR. An efficient and accurate methodology was applied, combining long-read sequencing and transcript analysis for the rapid characterization of the duplication. Results: Duplication of exons 5 and 6 of PALB2 was validated by transcript analysis. Long-read sequencing enabled the localization of breakpoints within Alu elements, providing insights into the mechanism of duplication via non-allelic homologous recombination. Conclusion: Using our combined methodology, we reclassified the PALB2 duplication as a pathogenic variant. This reclassification suggests a possible causative link between this specific genetic alteration and the aggressive phenotype of the patient.

Molecular Changes Associated with Suicide.

Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.

Novel insight into histological and molecular astrocytoma, IDH-mutant, Grade 4 by the updated WHO classification of central nervous system tumors.

BACKGROUND: The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021 defined astrocytoma, IDH-mutant, Grade 4. However, the understanding of this subtype is still limited. We conducted this study to describe the features of astrocytoma, IDH-mutant, Grade 4 and explored the similarities and differences between histological and molecular subtypes. METHODS: Patients who underwent surgery from January 2011 to January 2022, classified as astrocytoma, IDH-mutant, Grade 4 were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis. RESULTS: Altogether 33 patients with astrocytoma, IDH-mutant, Grade 4 were selected, including 20 with histological and 13 with molecular WHO Grade 4 astrocytoma. Tumor enhancement, intratumoral-necrosis like presentation, larger peritumoral edema, and more explicit tumor margins were frequently observed in histological WHO Grade 4 astrocytoma. Additionally, molecular WHO Grade 4 astrocytoma showed a tendency for relatively longer overall survival, while a statistical significance was not reached (47 vs. 25 months, p = 0.22). TP53, CDK6, and PIK3CA alteration was commonly observed, while PIK3R1 (p = 0.033), Notch1 (p = 0.027), and Mycn (p = 0.027) alterations may affect the overall survival of molecular WHO Grade 4 astrocytomas. CONCLUSIONS: Our study scrutinized IDH-mutant, Grade 4 astrocytoma. Therefore, further classification should be considered as the prognosis varied between histological and molecular WHO Grade 4 astrocytomas. Notably, therapies aiming at PIK3R1, Notch 1, and Mycn may be beneficial.

Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors.

Introduction: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors. This study aimed to characterize the clinical, radiological, molecular, and survival features of GBM under the current classification scheme and explore survival determinants. Methods: We re-examined the genetic alterations of IDH-wildtype diffuse gliomas at our institute from 2011 to 2022, and enrolled GBMs for analysis after re-classification. Univariable and multivariable analyses were used to identify survival determinants. Results: Among 209 IDH-wildtype gliomas, 191 were GBMs, including 146 hist-GBMs (76%) and 45 mol-GBMs (24%). Patients with mol-GBMs were younger, less likely to develop preoperative motor dysfunction, and more likely to develop epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences of contrast enhancement and intratumoral necrosis. Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN, with distinct patterns observed between the two subtypes. The median overall survival (mOS) of GMB was 12.6 months. Mol-GBMs had a higher mOS than hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement of deep brain structure or functional area, and genetic alterations in CDK4, CDK6, CIC, FGFR3, KMT5B, and MYB were predictors for a worse prognosis, while MGMT promoter methylation, maximal tumor resection, and treatment based on the Stupp protocol were predictive for better survival. Conclusion: The definition of GBM and its clinical, radiological, molecular, and prognostic characteristics have been altered under the current classification.

Are FGFR and IDH1-2 alterations a positive prognostic factor in intrahepatic cholangiocarcinoma? An unresolved issue.

Despite representing some of the most common and investigated molecular changes in intrahepatic cholangiocarcinoma (iCCA), the prognostic role of FGFR and IDH1/2 alterations still remains an open question. In this review we provide a critical analysis of available literature data regarding this topic, underlining the strengths and pitfalls of each study reported. Despite the overall poor quality of current available studies, a general trend toward a better overall survival for FGFR2 rearrangements and, possibly, for FGFR2-3 alterations can be inferred. On the other hand, the positive prognostic role of IDH1/2 mutation seems much more uncertain. In this scenario, better designed clinical trials in these subsets of iCCA patients are needed in order to get definitive conclusions on this issue.

Clinical updates on gliomas and implications of the 5th edition of the WHO classification of central nervous system tumors.

Background: The 5th edition of the World Health Organization (WHO) classification of central nervous system tumors incorporated specific molecular alterations into the categorization of gliomas. The major revision of the classification scheme effectuates significant changes in the diagnosis and management of glioma. This study aimed to depict the clinical, molecular, and prognostic characteristics of glioma and its subtypes according to the current WHO classification. Methods: Patients who underwent surgery for glioma at Peking Union Medical College Hospital during 11 years were re-examined for tumor genetic alterations using next-generation sequencing, polymerase chain reaction-based assay, and fluorescence in situ hybridization methods and enrolled in the analysis. Results: The enrolled 452 gliomas were reclassified into adult-type diffuse glioma (ntotal=373; astrocytoma, n=78; oligodendroglioma, n=104; glioblastoma, n=191), pediatric-type diffuse glioma (ntotal=23; low-grade, n=8; high-grade, n=15), circumscribed astrocytic glioma (n=20), and glioneuronal and neuronal tumor (n=36). The composition, definition, and incidence of adult- and pediatric-type gliomas changed significantly between the 4th and the 5th editions of the classification. The clinical, radiological, molecular, and survival characteristics of each subtype of glioma were identified. Alterations in CDK4/6, CIC, FGFR2/3/4, FUBP1, KIT, MET, NF1, PEG3, RB1, and NTRK2 were additional factors correlated with the survival of different subtypes of gliomas. Conclusions: The updated WHO classification based on histology and molecular alterations has updated our understanding of the clinical, radiological, molecular, survival, and prognostic characteristics of varied subtypes of gliomas and provided accurate guidance for diagnosis and potential prognosis for patients.

[Oesogastric cancer - new therapeutic targets]. / Adénocarcinome œsogastrique ­ nouvelles cibles thérapeutiques.

The median overall survival of metastatic esophagogastric adenocarcinoma is approximately twelve months. In fifteen years, major breakthrough have been the targeting of HER2 overexpression and more recently immunotherapy in patients with CPS≥5. Recent advances in molecular biology have identified some molecular alterations in esophageal adenocarcinoma, interesting to target. FGFR2 is overexpressed in one third of patients, and its targeting with a specific monoclonal antibody bemarituzumab showed a significant improvement in survival. Claudin 18.2 (CLDN 18.2) is overexpressed in at least a third of esophagogastric adenocarcinomas. The combination of zolbetuximab and chemotherapy provides a survival benefit, correlated with the intensity of CLDN 18.2 expression. The potential interest of targeting other pathways is under investigation in several trials with some encouraging preliminary data, and early trials in these indications, justifying considering large molecular screening in patients who might be candidate for early phase trial. Finally, with the recent advent of immunotherapy, one of the future challenges will be to optimize it through combination strategies with targeted therapies. The combination of anti-angiogenic and immunotherapy seems promising in gastric cancer.

Clinical and molecular features of disseminated pediatric low-grade glioma and glioneuronal tumors: a systematic review and survival analysis.

Background: Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT. Methods: A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively. Results: Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. Conclusions: Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders.

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

Enhancing the Catalytic Performance of Candida antarctica Lipase B by Chemical Modification With Alkylated Betaine Ionic Liquids.

Various betaine ionic liquids composed of different chain lengths and different anions were designed and synthesized to modify Candida antarctica lipase B (CALB). The results showed that the catalytic activity of all modified lipases improved under different temperature and pH conditions, while also exhibiting enhanced thermostability and tolerance to organic solvents. With an increase in ionic liquid chain length, the modification effect was greater. Overall, CALB modified by [BetaineC16][H2PO4] performed best, with the modified CALB enzyme activity increased 3-fold, thermal stability increased 1.5-fold when stored at 70°C for 30 min, with tolerance increased 2.9-fold in 50% DMSO and 2.3-fold in 30% mercaptoethanol. Fluorescence and circular dichroism (CD) spectroscopic analysis showed that the introduction of an ionic liquid caused changes in the microenvironment surrounding some fluorescent groups and the secondary structure of the CALB enzyme protein. In order to establish the enzyme activity and stability change mechanisms of the modified CALB, the structures of CALB modified with [BetaineC4][Cl] and [BetaineC16][Cl] were constructed, while the reaction mechanisms were studied by molecular dynamics simulations. Results showed that the root mean square deviation (RMSD) and total energy of modified CALB were less than those of native CALB, indicating that modified CALB has a more stable structure. Root mean square fluctuation (RMSF) calculations showed that the rigidity of modified CALB was enhanced. Solvent accessibility area (SASA) calculations exhibited that both the hydrophilicity and hydrophobicity of the modified enzyme-proteins were improved. The increase in radial distribution function (RDF) of water molecules confirmed that the number of water molecules around the active sites also increased. Therefore, modified CALB has enhanced structural stability and higher hydrolytic activity.

Analysis of somatic copy number alterations in biliary tract carcinoma using a single nucleotide polymorphism array.

AIM: Biliary tract carcinoma (BTC), including gall bladder carcinoma (GBC) and biliary duct carcinoma (BDC), has a poor prognosis. Comprehensive genomic profiling has important roles in evaluation of the carcinogenesis of BTC. MATERIALS & METHODS: We examined somatic copy number alterations (SCNAs) using a single nucleotide polymorphism array system to analyze 36 BTC samples (11 GBCs and 25 BDCs). RESULTS: In hierarchical cluster analysis, two clusters were identified (subgroup 1 with low SCNAs and subgroup 2 with high SCNAs). GBC was predominant in subgroup 1, whereas BDC was predominant in subgroup 2, suggesting that GBC and BDC had different genetic backgrounds in terms of SCNAs. CONCLUSION: These findings could be helpful for establishing the molecular carcinogenesis of BTCs.

Molecular toxicological alterations in the mouse hearts induced by sub-chronic thiazolidinedione drugs administration.

Thiazolidinediones are well-known anti-diabetic drugs. However, they are not widely used due to their cardiotoxic effects. Therefore, in this study, we aimed to determine the molecular toxicological alterations induced in the mouse hearts after thiazolidinedione administration. Balb/c mice received doses clinically equivalent to those given to humans of the most commonly used thiazolidinediones, pioglitazone, and rosiglitazone for 30 days. After that, RNA samples were isolated from the hearts. The mRNA expression of cytochrome (cyp) p450 genes that synthesize the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE) in addition to 92 cardiotoxicity biomarker genes were analyzed using quantitative polymerase chain reaction array technique. The analysis demonstrated that thiazolidinediones caused a significant upregulation (p < 0.5) of the mRNA expression of cyp1a1, cyp4a12, itpr1, ccl7, ccr1, and b2 m genes. In addition, thiazolidinediones caused a significant (p < 0.05) downregulation of the mRNA expression of adra2a, bsn, col15a1, fosl1, Il6, bpifa1, plau, and reg3b genes. The most affected gene was itpr1 gene, which was upregulated by pioglitazone and rosiglitazone by sevenfold and 3.5-fold, respectively. In addition, pioglitazone caused significant upregulation of (p < 0.05) hamp, ppbp, psma2, sik1, timp1, and ucp1 genes, which were not affected significantly (p > 0.05) by rosiglitazone administration. In conclusion, this study showed that thiazolidinediones induce toxicological molecular alterations in the mouse hearts, such as the induction of cyp450s that synthesize 20-HETE, chemokine activation, inflammatory responses, blood clotting, and oxidative stress. These findings may help us understand the mechanism of cardiotoxicity involved in thiazolidinedione administration.

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches.

Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

Molecular Alterations in Lung Adenocarcinoma With Ground-Glass Nodules: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Nodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression. METHODS: Studies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data. RESULTS: A total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene (51%, 95%CI 47%-56%), followed by TP53 (18%, 95%CI 6%-31%), HER2 (10%, 95%CI 0%-21%), ROS1 (6%, 95%CI 0%-18%), and KRAS (6%, 95%CI 3%-9%). The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI [38.48%; 56.40%]; sGGO 51.94%, 95%CI [45.15%; 58.69%]. The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI [1.35%; 6.13%]; sGGO 12.27%, 95%CI [3.89%; 23.96%]. The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%-13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES. CONCLUSIONS: Somatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs.