-
The New England Journal of Medicine Jun 2021The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.
METHODS
In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.
RESULTS
A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.
CONCLUSIONS
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; B7-H1 Antigen; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Nivolumab; Placebos; Quality of Life; Urinary Bladder Neoplasms
PubMed: 34077643
DOI: 10.1056/NEJMoa2034442 -
Cell Oct 2021Unprecedented advances have been made in cancer treatment with the use of immune checkpoint blockade (ICB). However, responses are limited to a subset of patients, and... (Review)
Review
Unprecedented advances have been made in cancer treatment with the use of immune checkpoint blockade (ICB). However, responses are limited to a subset of patients, and immune-related adverse events (irAEs) can be problematic, requiring treatment discontinuation. Iterative insights into factors intrinsic and extrinsic to the host that impact ICB response and toxicity are critically needed. Our understanding of the impact of host-intrinsic factors (such as the host genome, epigenome, and immunity) has evolved substantially over the past decade, with greater insights on these factors and on tumor and immune co-evolution. Additionally, we are beginning to understand the impact of acute and cumulative exposures-both internal and external to the host (i.e., the exposome)-on host physiology and response to treatment. Together these represent the current day hallmarks of response, resistance, and toxicity to ICB. Opportunities built on these hallmarks are duly warranted.
Topics: Animals; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Immune Checkpoint Proteins; Immunity; Immunotherapy; Neoplasms
PubMed: 34624224
DOI: 10.1016/j.cell.2021.09.020 -
Nature Jan 2020Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have...
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity, although these have been less well-studied in ICB treatment. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
Topics: B-Lymphocytes; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Cycle Checkpoints; Clone Cells; Dendritic Cells, Follicular; Gene Expression Regulation, Neoplastic; Humans; Immunologic Memory; Immunotherapy; Mass Spectrometry; Melanoma; Neoplasm Metastasis; Phenotype; Prognosis; RNA-Seq; Receptors, Immunologic; Single-Cell Analysis; T-Lymphocytes; Tertiary Lymphoid Structures; Transcriptome
PubMed: 31942075
DOI: 10.1038/s41586-019-1922-8 -
Cureus Aug 2022Ameloblastoma is one of the most common benign odontogenic tumors of the jaw that constitutes about 10% of all tumors that arise in the mandible and maxilla. It is a... (Review)
Review
Ameloblastoma is one of the most common benign odontogenic tumors of the jaw that constitutes about 10% of all tumors that arise in the mandible and maxilla. It is a slow-growing but locally invasive tumor that presents with painless swelling of the mandible or maxilla. The World Health Organization (WHO) classification of 2017 describes ameloblastomas of the following four types: ameloblastoma; unicystic ameloblastoma; extraosseous/peripheral ameloblastoma; and metastasizing ameloblastoma. The diagnosis of ameloblastoma requires computerized tomography (CT) imaging as well as a biopsy. A biopsy is helpful in differentiating ameloblastoma from ossifying fibroma, osteomyelitis, giant cell tumor, cystic fibrous dysplasia, myeloma, and sarcoma. The best treatment of ameloblastoma is aggressive en bloc resection with simultaneous reconstruction. The high recurrence rate and large tissue defects have been long-standing issues in the treatment of ameloblastoma. Recent molecular developments strongly suggest the possibility of targeted therapy with better outcomes in ameloblastomas. We present a detailed updated narrative review of our current understanding and management of this enigmatic tumor.
PubMed: 36127985
DOI: 10.7759/cureus.27734 -
The Journal of Clinical Endocrinology... Apr 2022Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM).... (Review)
Review
CONTEXT
Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ).
OBJECTIVE
We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them.
METHODS
A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with BM.
RESULTS
The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients.
CONCLUSION
The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Diphosphonates; Humans; Jaw; Syndrome
PubMed: 34922381
DOI: 10.1210/clinem/dgab888 -
Head and Neck Pathology Mar 2022The World Health Organization Classification of Head and Neck Tumours recently published the 5th edition. There are new entities, emerging entities, and significant... (Review)
Review
The World Health Organization Classification of Head and Neck Tumours recently published the 5th edition. There are new entities, emerging entities, and significant updates to the taxonomy and characterization of tumor and tumor-like lesions, specifically in this article as it relates to nasal cavity, paranasal sinuses and skull base. Importantly, the number of diagnostic entries has been reduced by creating category-specific chapters for soft tissue, hematolymphoid, melanocytic, neuroectodermal, and metastatic tumors. Bone and salivary gland tumors are also not separately reported in the sinonasal tract, but included in the jaw and salivary gland sections, respectively. Repetition of characteristic entities in each anatomic site was also reduced, instead highlighting only the unique features in each anatomic site. Two new entities (SWI/SNF complex-deficient sinonasal carcinomas and HPV-related multiphenotypic sinonasal carcinoma) will be highlighted in this review, with a discussion of several emerging entities. There is a short description of updated information for all 24 diagnostic entities included in this edition to allow the reader a snapshot of current state of knowledge, but to encourage more investigation and further broaden understanding of these diverse and rare entities.
Topics: Carcinoma; Humans; Nasal Cavity; Paranasal Sinus Neoplasms; Paranasal Sinuses; Skull Base; World Health Organization
PubMed: 35312976
DOI: 10.1007/s12105-021-01406-5 -
Head and Neck Pathology Mar 2022The initiative of the 5th edition of the WHO classification of the Head and Neck Tumours establishing a new section dedicated to familial/heritable tumor syndromes with... (Review)
Review
The initiative of the 5th edition of the WHO classification of the Head and Neck Tumours establishing a new section dedicated to familial/heritable tumor syndromes with tumors and lesions in the head and neck region was much needed to better understand the tumours, diseases, and associated syndromes, as well as establish recommendations for monitoring and treating these patients. (WHO Classification of Tumours Editorial Board. Head and Neck tumours. Lyon (France): International Agency for Research on Cancer; 2022. https://publications.iarc.fr/ ). Within the newly established chapter on genetic tumor syndromes, we have described the main manifestations on the head and neck region in 15 syndromes. This review highlights the important findings within these syndromes, especially on the update on syndromes with tumors involving the head and neck region, as Gorlin syndrome/nevoid basal cell carcinoma syndrome associated with odontogenic keratocysts; Brooke-Spiegler syndrome/familial cylindromatosis and the associated membranous-type salivary gland basal cell adenoma, PTEN hamartoma tumor syndrome/Cowden syndrome with associated facial skin and mucosal lesions and characteristic multinodular thyroid lesions, Von Hippel Lindau syndrome and the associated middle ear endolymphatic sac tumor, as well as the fascinating genetic aspects of the diverse Head and Neck Paragangliomas. We will also discuss hyperparathyroidism-jaw tumor syndrome is characterized by parathyroid tumors in association with fibro-osseous jaw tumors, as well as head and neck desmoid tumors associated with familial adenomatous polyposis with Gardner syndrome variant familial, multicentric head and neck squamous cell carcinoma, tuberous sclerosis and neurofibromatosis type 1-associated head and neck lesions.
Topics: Basal Cell Nevus Syndrome; Hamartoma Syndrome, Multiple; Head and Neck Neoplasms; Humans; Neoplastic Syndromes, Hereditary; Skin Neoplasms; World Health Organization
PubMed: 35312981
DOI: 10.1007/s12105-022-01414-z -
Bone Dec 2021Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been... (Review)
Review
Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.
Topics: Animals; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Diphosphonates; Disease Models, Animal; Dogs; Humans; Mice; Rabbits; Rats; Sheep; Swine
PubMed: 34520898
DOI: 10.1016/j.bone.2021.116184 -
European Journal of Paediatric Dentistry Sep 2020Odontomas are hamartomatous developmental malformations of the dental tissues. Usually asymptomatic, their presence is often revealed on routine radiographs. The study... (Review)
Review
BACKGROUND
Odontomas are hamartomatous developmental malformations of the dental tissues. Usually asymptomatic, their presence is often revealed on routine radiographs. The study aimed to establish the efficacy of this conventional approach in treating odontomas, analysing clinical outcome, follow-up, and histomorphological profile.
CASE REPORT
A case is presented with a review of the international literature. The patient, aged 8 years, had a complex odontoma localised on the front upper jaw. She was treated following the conventional surgical procedure. Post-operative course and healing were uneventful. Orthodontic treatment was necessary to realign the teeth. At the 12-month follow-up there was no recurrence or failure. Healing was excellent.
CONCLUSION
Variations in normal tooth eruption are a common finding, but significant deviations from established norms should alert the clinician to further investigate the patient's health and development.
Topics: Child; Female; Humans; Maxilla; Neoplasm Recurrence, Local; Odontoma; Tooth Eruption; Tooth, Impacted
PubMed: 32893652
DOI: 10.23804/ejpd.2020.21.03.08