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Cureus Jan 2024Cystadenomas are benign neoplasms found in major and minor salivary glands. In cases where both oncocytic cells and papillary architecture, without a lymphoid...
Cystadenomas are benign neoplasms found in major and minor salivary glands. In cases where both oncocytic cells and papillary architecture, without a lymphoid component, exist, the lesion is called oncocytic papillary cystadenoma (OPC). OPCs are rarely encountered in the laryngeal region and that is why they are usually misdiagnosed as other types of laryngeal tumors. Hereby, we present a case of a misdiagnosed laryngeal OPC in an attempt to raise awareness of this rare entity, both for the surgeon performing the excision of the laryngeal mass and for the pathologists examining the specimen.
PubMed: 38344518
DOI: 10.7759/cureus.52147 -
Current Problems in Cancer Apr 2024The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR,... (Review)
Review
The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging. For example, MEK inhibition - when combined with BRAF inhibition, - has shown strong anti-tumor activity in BRAF V600 mutated NSCLC. In this review, recent data on MEK inhibitor strategies in NSCLC are summarized. Furthermore, ongoing early phase trials investigating MEK inhibitor combination therapy with immunotherapy, chemotherapy and other oncogene drivers are highlighted. These and other studies could help inform future rational combination strategies of MEK-ERK inhibition in oncogene-driven NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; Molecular Targeted Therapy; Antineoplastic Combined Chemotherapy Protocols; MAP Kinase Signaling System; Mutation
PubMed: 38341356
DOI: 10.1016/j.currproblcancer.2024.101065 -
Asian Journal of Surgery May 2024
Topics: Female; Humans; Male; Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Adenoma; Adrenocortical Carcinoma; Diagnostic Errors; Tomography, X-Ray Computed; Adult
PubMed: 38302362
DOI: 10.1016/j.asjsur.2024.01.098 -
Breast Cancer Research : BCR Jan 2024Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC.
METHODS
We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR).
RESULTS
Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells.
CONCLUSION
In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target.
TRIAL REGISTRATION
www.
CLINICALTRIALS
gov , NCT02876302. Registered 23 August 2016.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Inflammatory Breast Neoplasms; Interleukin-6; Neoadjuvant Therapy; Nitriles; Paclitaxel; Pyrazoles; Pyrimidines; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 38297352
DOI: 10.1186/s13058-024-01774-0 -
Endocrine Pathology Mar 2024Cytosine modifications at the 5-carbon position play a critical role in gene expression regulation and have been implicated in cancer development....
Cytosine modifications at the 5-carbon position play a critical role in gene expression regulation and have been implicated in cancer development. 5-Hydroxymethylcytosine (5hmC), arising from 5-methylcytosine (5-mC) oxidation, has shown promise as a potential malignancy marker due to its depletion in various human cancers. However, its significance in thyroid tumors remains underexplored, primarily due to limited data. In our study, we evaluated 5hmC expression levels by immunohistochemistry in a cohort of 318 thyroid tumors. Our analysis revealed significant correlations between 5hmC staining extension scores and nodule size, vascular invasion, and oncocytic morphology. Nuclear 5hmC staining intensity demonstrated associations with focality, capsule status, extrathyroidal extension, vascular invasion, and oncocytic morphology. Follicular/oncocytic adenomas exhibited higher 5hmC expression than uncertain malignant potential (UMP) or noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), as well as malignant neoplasms, including papillary thyroid carcinomas (PTCs), oncocytic carcinomas (OCAs), follicular thyroid carcinomas (FTCs), and invasive encapsulated follicular variants of PTC (IEFV-PTC). TERT promoter mutation cases showed notably lower values for the 5hmC expression, while RAS (H, N, or K) mutations, particularly HRAS mutations, were associated with higher 5hmC expression. Additionally, we identified, for the first time, a significant link between 5hmC expression and oncocytic morphology. However, despite the merits of these discoveries, we acknowledge that 5hmC currently cannot segregate minimally invasive from widely invasive tumors, although 5hmC levels were lower in wi-FPTCs. Further research is needed to explore the potential clinical implications of 5hmC in thyroid tumors.
Topics: Humans; 5-Methylcytosine; Thyroid Neoplasms; Adenocarcinoma, Follicular; Biomarkers, Tumor; Epigenesis, Genetic
PubMed: 38285158
DOI: 10.1007/s12022-024-09800-9 -
Cancer Cell Feb 2024Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained...
Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; DNA Methylation; Cell-Free Nucleic Acids; Epigenesis, Genetic; Biomarkers, Tumor
PubMed: 38278149
DOI: 10.1016/j.ccell.2024.01.001 -
Turk Patoloji Dergisi 2024The classification of renal tumors is expanding with the addition of new molecular entities in the 5th World Health Organization classification. Apart from this, the...
OBJECTIVE
The classification of renal tumors is expanding with the addition of new molecular entities in the 5th World Health Organization classification. Apart from this, the major updates in the definition of papillary renal cell carcinoma are that these tumors are no longer subtyped into type 1 and type 2. In oncocytic tumors, the new molecularly defined renal tumors, emerging and novel entities need to be considered in the diagnosis of oncocytic and chromophobe renal tumors.
MATERIAL AND METHODS
This is a retrospective study to review and reclassify papillary, oncocytic, and chromophobe renal tumors based on the new WHO classification and correlate with clinical data, gross, microscopic features, and immunohistochemistry markers.
RESULTS
A total of thirteen cases were reviewed and the tumor grade was changed for three out of four cases of papillary renal cell carcinoma and a single case was recategorized and graded. In nine cases of oncocytic and chromophobe renal tumors, the diagnoses were modified in 3 cases.
CONCLUSION
Newly defined molecular renal tumors require advanced immunohistochemistry markers and molecular tests. This poses diagnostic challenges to pathologists practicing in low resource settings where molecular tests are not available.
Topics: Humans; Kidney Neoplasms; Retrospective Studies; Male; Female; Carcinoma, Renal Cell; Middle Aged; Aged; World Health Organization; Biomarkers, Tumor; Adult; Immunohistochemistry; Adenoma, Oxyphilic; Neoplasm Grading
PubMed: 38265103
DOI: 10.5146/tjpath.2024.13052 -
Frontiers in Endocrinology 2023The radioiodine-refractory (RAI-R) recurrent papillary thyroid carcinomas (PTCs) are more frequent in elderly patients and have an unfavorable prognosis. Data on the...
INTRODUCTION
The radioiodine-refractory (RAI-R) recurrent papillary thyroid carcinomas (PTCs) are more frequent in elderly patients and have an unfavorable prognosis. Data on the prevalence and characteristics of RAI-R recurrent PTCs in patients of young and middle age with or without a history of radiation exposure in childhood are poorly described. The aim of the current study was: i) to determine the frequency of RAI-R recurrent PTCs among donors of the Chornobyl Tissue Bank (CTB) and analyze the clinicopathological features of primary tumors (PTs), primary metastases (PMTSs), recurrent metastases (RMTSs) and risk factors for RMTS, and ii) to determine the immune checkpoint status (ICS) of the RAI-R recurrent PTCs and to assess the factors associated with ICS positivity.
METHODS
Sixty RAI-R recurrent PTCs (46 exposed to radiation and 14 non-exposed, 2.5% of all cases registered with the CTB) from the Ukrainian patients aged up to 48 years were identified.
RESULTS
The clinicopathological characteristics of the PTs moderately to weakly resembled those of the PMTS and RMTS from the same patients while the metastatic tissues were highly similar. The multivariate model of RMTS included the dominant solid-trabecular growth pattern of the PT, cystic changes, N1b metastases, and the probability of a causation (POC) of PTC by radiation as risk factors. Among these factors, the lateral PMTS (N1b) had the strongest effect. The longer period of latency (a POC component) was the second statistically significant characteristic. ICS percent agreement between the PT and RAI-R RMTS was 91.5%; 23.7% of PTs and 28.8% of RMTSs had positive ICS (positive PD-L1 tumor epithelial cells (TECs) and positive PD-L1/PD1 tumor-associated immune cells). ICS positivity of PTs was associated with pronounced oncocytic changes and high density of the p16-positive TECs in the invasive areas of PTs. In RMTSs, ICS positivity was associated with pronounced oncocytic changes and Ki-67 labeling index ≥ 4.5% of PTs, and the dominant solid-trabecular growth pattern, Ki-67 labeling index ≥ 7.6% and p16-positivity of RMTS.
DISCUSSION
The findings are of clinical relevance and may be useful for developing individual treatment approaches for patients with RAI-R recurrent PTCs possibly involving immunotherapy.
Topics: Aged; Middle Aged; Humans; Thyroid Cancer, Papillary; B7-H1 Antigen; Iodine Radioisotopes; Chernobyl Nuclear Accident; Cyclin-Dependent Kinase Inhibitor p16; Ki-67 Antigen; Neoplasm Recurrence, Local; Thyroid Neoplasms
PubMed: 38260161
DOI: 10.3389/fendo.2023.1343848 -
Current Oncology (Toronto, Ont.) Jan 2024Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes...
Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Analgesics, Opioid; Immune Checkpoint Inhibitors; Duration of Therapy; Lung Neoplasms; Opioid-Related Disorders
PubMed: 38248102
DOI: 10.3390/curroncol31010017 -
European Journal of Medical Research Jan 2024N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our...
BACKGROUND
N-Nitrosomorpholine (NMO) is one of the most common N-nitroso compounds. An oncocytic transformation has been demonstrated in renal tubules of NMO-treated rats. In our study, we aimed to investigate the potential transformation of oncocytic cells in 6 endocrine organs, i.e., thyroid, adrenal and pituitary glands, pancreas, testis, and bone, of NMO-exposed rats.
METHODS
Thirty male rats were born and raised. Fifteen of them were given a single dose of 320 mg NMO per kg body weight, dissolved in drinking water, by a gavage tube. At the end of 52 weeks, the animals in both series were killed. Right after the killing, 6 different endocrine organs (hypophysis, thyroid, pancreas, adrenal gland, bone [femur], and testicles) of each animal were excised.
RESULTS
There was no evidence of oncocytic cell development in the control group. In contrast, oncocytes were observed in 8 out of 13 NMO-treated rats: 2 in the adrenal sections, 1 in the thyroid sections, 3 in the pituitary sections, and 2 in the pancreas sections. Thesticle and bone sections were completely normal.
CONCLUSIONS
We showed that NMO induced an oncocytic change in pancreas, thyroid, pituitary, and adrenal glands. To date, no identified specific environmental risk factors that lead to an oncocytic transformation in endocrine glands have been reported previously. Given the increasing prevalence of endocrine-disrupting chemicals in the environment, personal care products, manufactured goods, and food sources, there is a need to advance our understanding of the pathological mechanisms underlying oncocytosis in endocrine organs.
Topics: Rats; Male; Animals; Oxyphil Cells; Nitrosamines; Thyroid Gland; Adrenal Glands
PubMed: 38245764
DOI: 10.1186/s40001-024-01654-5