-
Nature Sep 2023Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear. Because ICB...
Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear. Because ICB targets cell-cell interactions, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8TCF1T cells and MHCII cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B T cells. On-treatment, responsive tumours contained abundant granzyme B T cells, whereas resistant tumours were characterized by CD15 cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.
Topics: Humans; B-Lymphocytes; Biopsy; CD8-Positive T-Lymphocytes; Granzymes; Histocompatibility Antigens Class II; Immunotherapy; Lewis X Antigen; Neoadjuvant Therapy; Precision Medicine; Prognosis; Randomized Controlled Trials as Topic; T-Lymphocytes; Triple Negative Breast Neoplasms
PubMed: 37674077
DOI: 10.1038/s41586-023-06498-3 -
Endocrine-related Cancer Nov 2023Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in...
Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in ITN. Post-validation studies are necessary to determine the real-world clinical benefit of ThyroidPrint® in patients with ITN. A single-center, prospective, noninterventional clinical utility study was performed, analyzing the impact of ThyroidPrint® in the physicians' clinical decisions for ITN. Demographics, nodule characteristics, benign call rates (BCRs), and surgical outcomes were measured. Histopathological data were collected from surgical biopsies of resected nodules. Of 1272 fine-needle aspirations, 109 (8.6%) were Bethesda III and 135 (10.6%) were Bethesda IV. Molecular testing was performed in 155 of 244 ITN (63.5%), of which 104 were classified as benign (BCR of 67.1%). After a median follow-up of 15 months, 103 of 104 (99.0%) patients with a benign ThyroidPrint® remained under surveillance and one patient underwent surgery which was a follicular adenoma. Surgery was performed in all 51 patients with a suspicious for malignancy as per ThyroidPrint® result and in 56 patients who did not undergo testing, with a rate of malignancy of 70.6% and 32.1%, respectively. A higher BCR was observed in follicular lesion of undetermined significance (87%) compared to atypia of undetermined significance (58%) (P < 0.05). False-positive cases included four benign follicular nodules and six follicular and four oncocytic adenomas. Our results show that, physicians chose active surveillance instead of diagnostic surgery in all patients with a benign ThyroidPrint® result, reducing the need for diagnostic surgery in 67% of patients with preoperative diagnosis of ITN.
Topics: Humans; Prospective Studies; Gene Expression Profiling; Retrospective Studies; Thyroid Neoplasms; Thyroid Nodule; Biopsy, Fine-Needle
PubMed: 37671897
DOI: 10.1530/ERC-22-0409 -
Frontiers in Endocrinology 2023The management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However,...
BACKGROUND
The management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However, in distinct types DTC, differences in RAI avidity and response existed and the effect of RAI therapy could not be equated.
METHODS
DTC patients' data in SEER database were extracted to perform retrospective analysis. The differences between case group and control group were compared by chi-square tests. We used Kaplan-Meier statistics and Cox regression analyses to investigate cancer-specific survival (CSS). Propensity score-matched was performed to make 1:1 case-control matching.
RESULTS
105195 patients who receiving total thyroidectomy were identified in SEER database. Compared to papillary thyroid carcinoma (PTC) (52.3%), follicular thyroid carcinoma (FTC) (63.8%) and oncocytic carcinoma of thyroid (OCA) (64.4%) had higher rates of RAI therapy. In the multivariable Cox regression model, RAI therapy was independent prognosis factor in PTC but not in OCA and FTC. In subgroup analysis, RAI therapy could improve prognosis in PTC when gross extrathyroidal extension or lymph node metastases or early survival when distant metastases (DM) were presented. However, OCA and FTC patients with DM rather than regional lesions only could benefit from RAI therapy. High-risk patients receiving RAI therapy showed a better prognosis in PTC but not in OCA and FTC.
CONCLUSION
RAI therapy was an effective treatment for DTC and should be considered individually in PTC, OCA and FTC patients. Our results provided further guideline for treatment selection in DTC.
Topics: Humans; Thyroid Neoplasms; Iodine Radioisotopes; Propensity Score; Retrospective Studies; Adenocarcinoma, Follicular; Thyroid Cancer, Papillary
PubMed: 37664843
DOI: 10.3389/fendo.2023.1158581 -
Journal of Cellular and Molecular... Sep 2023Head and neck squamous cell carcinomas (HNSCCs) are generally associated with tobacco consumption, alcohol abuse or both. Mucins (MUCs) are high-molecular-weight...
Head and neck squamous cell carcinomas (HNSCCs) are generally associated with tobacco consumption, alcohol abuse or both. Mucins (MUCs) are high-molecular-weight glycoproteins produced by many epithelial tissues. Many studies have indicated that MUCs play an important role in cancer metastasis. MUC6 expression has been observed in gastric and oncocytic phenotypes and plays an important role during cancer progression. We found that levels of MUC6 are lower in Asian HNCC patients and affect the disease-free survival of HNCC patients. Next, we investigated the combined effect of MUC6 polymorphisms and exposure to environmental carcinogens on the susceptibility to and clinicopathological characteristics of HNCC. Three single-nucleotide polymorphisms (SNPs) of MUC6 (rs7481521, rs6597947 and rs61869016) were analysed using real-time PCR. After adjusting for other co-variants, we found that carrying a CC genotype at MUC6 rs6597947 led to a lower risk of developing oral squamous cell carcinoma (OSCC) than wild-type carriers among non-betel-quid chewers. Moreover, male oral cancer patients who carried the AA + CC genotype at MUC6 rs6597947 had a lower risk of lymph node metastasis than other genotypes, suggesting a significant functional compromise and decompensated disease. Therefore, our findings suggest that genetic variations in MUC6 may correlate to OSCC and indicate the progression in OSCC patients.
Topics: Male; Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Mouth Neoplasms; Polymorphism, Single Nucleotide; Genotype; Head and Neck Neoplasms; Genetic Predisposition to Disease; Case-Control Studies; Risk Factors; Mucin-6
PubMed: 37581476
DOI: 10.1111/jcmm.17886 -
Medicine Aug 2023The study aimed to evaluate the ABO/Rh blood group distributions and their relationship with clinical-pathological features in papillary thyroid cancer patients. It was...
The study aimed to evaluate the ABO/Rh blood group distributions and their relationship with clinical-pathological features in papillary thyroid cancer patients. It was planned as a retrospective case-controlled study. The blood group distributions of the patients were contrasted with that of the general population. Additionally, the association between clinical-pathological variables and blood group distribution was assessed. Two hundred and ninety-three patients were involved in the study. The median age was 48 years, and the majority of patients were female (84.3%). The most common variants of papillary thyroid cancer were follicular, classical, and oncocytic. The majority of the patients had stage 1 (91.1%) disease at the time of diagnosis. ABO blood group distributions in the patient (47.4% A, 11.9% B, 8.2% AB, 32.4% O) and control (42% A, 16% B, 8% AB, 34% O) groups were found to be similar ( P = .8). In terms of Rh factor, there was a comparable distribution for the characteristics of the patient and healthy control group ( P = .6). There was no association between clinical and pathological variables and blood group distributions (gender, age, tumor stage, tumor location, and pathological tumor variant). Comparing patients with papillary thyroid carcinoma to the healthy control group, the prevalence of the A blood group numerically increased while the prevalence of the B blood group numerically decreased, but it was not statistically significant. In addition, ABO/Rh blood type and clinical and pathological variables did not relate.
Topics: Humans; Male; Female; Middle Aged; ABO Blood-Group System; Rh-Hr Blood-Group System; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 37565904
DOI: 10.1097/MD.0000000000034564 -
The Oncologist Nov 2023CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to...
BACKGROUND
CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors.
METHODS
Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%.
RESULTS
Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls.
CONCLUSION
Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).
Topics: Humans; Male; Female; Etoposide; Carboplatin; Small Cell Lung Carcinoma; Lung Neoplasms; Bayes Theorem; Neutropenia; Thrombocytopenia; Anemia; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37555284
DOI: 10.1093/oncolo/oyad221 -
Scientific Reports Aug 2023Differentiating benign renal oncocytic tumors and malignant renal cell carcinoma (RCC) on imaging and histopathology is a critical problem that presents an everyday...
Differentiating benign renal oncocytic tumors and malignant renal cell carcinoma (RCC) on imaging and histopathology is a critical problem that presents an everyday clinical challenge. This manuscript aims to demonstrate a novel methodology integrating metabolomics with radiomics features (RF) to differentiate between benign oncocytic neoplasia and malignant renal tumors. For this purpose, thirty-three renal tumors (14 renal oncocytic tumors and 19 RCC) were prospectively collected and histopathologically characterised. Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) was used to extract metabolomics data, while RF were extracted from CT scans of the same tumors. Statistical integration was used to generate multilevel network communities of -omics features. Metabolites and RF critical for the differentiation between the two groups (delta centrality > 0.1) were used for pathway enrichment analysis and machine learning classifier (XGboost) development. Receiver operating characteristics (ROC) curves and areas under the curve (AUC) were used to assess classifier performance. Radiometabolomics analysis demonstrated differential network node configuration between benign and malignant renal tumors. Fourteen nodes (6 RF and 8 metabolites) were crucial in distinguishing between the two groups. The combined radiometabolomics model achieved an AUC of 86.4%, whereas metabolomics-only and radiomics-only classifiers achieved AUC of 72.7% and 68.2%, respectively. Analysis of significant metabolite nodes identified three distinct tumour clusters (malignant, benign, and mixed) and differentially enriched metabolic pathways. In conclusion, radiometabolomics integration has been presented as an approach to evaluate disease entities. In our case study, the method identified RF and metabolites important in differentiating between benign oncocytic neoplasia and malignant renal tumors, highlighting pathways differentially expressed between the two groups. Key metabolites and RF identified by radiometabolomics can be used to improve the identification and differentiation between renal neoplasms.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Tomography, X-Ray Computed; Machine Learning; ROC Curve; Brain Neoplasms; Retrospective Studies
PubMed: 37537362
DOI: 10.1038/s41598-023-39809-9 -
Journal For Immunotherapy of Cancer Aug 2023Dysthyroidism (DT) is a common toxicity of immune checkpoint inhibitors (ICIs) and prior work suggests that dysthyroidism (DT) might be associated with ICI efficacy.
BACKGROUND
Dysthyroidism (DT) is a common toxicity of immune checkpoint inhibitors (ICIs) and prior work suggests that dysthyroidism (DT) might be associated with ICI efficacy.
PATIENTS AND METHODS
ConSoRe, a new generation data mining solution, was used in this retrospective study, to extract data from electronic patient records of adult cancer patients treated with ICI at Institut Paoli-Calmettes (Marseille, France). Every DT was verified and only ICI-induced DT was retained. Survival analyses were performed by Kaplan-Meier method (log-rank test) and Cox model. To account for immortal time bias, a conditional landmark analysis was performed (2 months and 6 months), together with a time-varying Cox model.
RESULTS
Data extraction identified 1385 patients treated with ICI between 2011 and 2021. DT was associated with improved overall survival (OS) (HR 0.46, (95% CI 0.33 to 0.65), p<0.001), with a median OS of 35.3 months in DT group vs 15.4 months in non-DT group (NDT). Survival impact of DT was consistent using a 6-month landmark analysis with a median OS of 36.7 months (95% CI 29.4 to not reported) in the DT group vs 25.5 months (95% CI 22.8 to 27.8) in the NDT group. In multivariate analysis, DT was independently associated with improved OS (HR 0.49, 95% CI 0.35 to 0.69, p=0.001). After adjustment in time-varying Cox model, this association remained significant (adjusted HR 0.64, 95% CI 0.45 to 0.90, p=0.010). Moreover, patients with DT and additional immune-related adverse event had increased OS compared with patients with isolated DT, with median OS of 38.8 months vs 21.4 months, respectively.
CONCLUSION
Data mining identified a large number of patients with ICI-induced DT, which was associated with improved OS accounting for immortal time bias.
Topics: Humans; Adult; Immune Checkpoint Inhibitors; Electronic Health Records; Retrospective Studies; Neoplasms; Data Mining
PubMed: 37536938
DOI: 10.1136/jitc-2023-006786 -
Indian Journal of Pathology &... 2023Neoplastic lipomatous lesions of the salivary glands constitute ≤0.5% of all the salivary gland tumors. Oncocytic sialolipoma of the parotid glands is extremely... (Review)
Review
Neoplastic lipomatous lesions of the salivary glands constitute ≤0.5% of all the salivary gland tumors. Oncocytic sialolipoma of the parotid glands is extremely uncommon. We report a case of oncocytic sialolipoma of the parotid gland in a 59-year-old male who presented with a gradually increasing swelling of the right parotid. Excisional parotid biopsy performed in view of possible pleomorphic adenoma as suggested on ultrasonography showed histological features consistent with oncocytic sialolipoma. We also described the characteristics of 24 previously reported cases of oncocytic sialolipoma of the parotid gland. The median age of the patients including the present case was 56 years (range 7-89), and 14 were male. The largest and the least reported sizes of the tumor were 7.0 and 1.4 cm, respectively. The left-sided parotid gland was more commonly involved (14/23). Despite its rarity, oncocytic sialolipoma should be considered in lipomatous parotid lesions showing epithelial components with oncocytic changes.
Topics: Humans; Male; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Parotid Gland; Adenoma; Salivary Gland Neoplasms; Oxyphil Cells; Lipoma; Parotid Neoplasms
PubMed: 37530346
DOI: 10.4103/ijpm.ijpm_323_21 -
Cancer Research Communications Jul 2023Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic...
UNLABELLED
Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.
SIGNIFICANCE
The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Uniparental Disomy; Oxyphil Cells; B7-H1 Antigen; Tumor Microenvironment
PubMed: 37529400
DOI: 10.1158/2767-9764.CRC-23-0120