-
Cell Reports. Medicine Mar 2024[F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide...
[F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly and not universally accessible, particularly in low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that can produce FDG-PET from diagnostic CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic PET images are validated across imaging, biological, and clinical aspects. Radiologists confirm comparable imaging quality and tumor contrast between synthetic and actual PET scans. Radiogenomics analysis further proves that the dysregulated cancer hallmark pathways of synthetic PET are consistent with actual PET. We also demonstrate the clinical values of synthetic PET in improving lung cancer diagnosis, staging, risk prediction, and prognosis. Taken together, this proof-of-concept study testifies to the feasibility of applying deep learning to obtain high-fidelity PET translated from CT.
Topics: Humans; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Lung Neoplasms; Tomography, X-Ray Computed; Prognosis
PubMed: 38471502
DOI: 10.1016/j.xcrm.2024.101463 -
Journal For Immunotherapy of Cancer Mar 2024Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody...
BACKGROUND
Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.
METHODS
CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments.
RESULTS
CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab.
CONCLUSIONS
Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer.
TRIAL REGISTRATION NUMBERS
NCT02110082; NCT02253992.
Topics: Humans; Nivolumab; Cetuximab; Melanoma; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms
PubMed: 38458639
DOI: 10.1136/jitc-2023-007364 -
Annales de Pathologie May 2024In 2022, the 5th edition of the WHO classification of Head and Neck tumors was published online. In the salivary gland chapter, a new benign entity, the keratocystoma,...
In 2022, the 5th edition of the WHO classification of Head and Neck tumors was published online. In the salivary gland chapter, a new benign entity, the keratocystoma, was introduced. The sclerosing polycystic adenosis has been recognized as tumoral and is now termed sclerosing polycystic adenoma. The striated duct adenoma now has its own dedicated chapter. Additionally, a new variant of pleomorphic adenoma, termed "canalicular adenoma-like," has been incorporated. Regarding malignant tumors of the salivary glands, significant doubts now exist regarding the actual existence of oncocytic carcinoma, which has been reclassified among emerging entities. Two new malignant entities have also emerged: microsecretory adenocarcinoma and microcystic sclerosing adenocarcinoma. Finally, primary mucinous adenocarcinoma of the salivary glands has been acknowledged as a distinct entity.
Topics: Humans; Salivary Gland Neoplasms; World Health Organization
PubMed: 38448262
DOI: 10.1016/j.annpat.2024.02.005 -
Nature Mar 2024Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. Here we studied 246,102...
Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8 alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8 cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.
Topics: Animals; Humans; Mice; Adenocarcinoma of Lung; Alveolar Epithelial Cells; Aneuploidy; Carcinogens; Cell Differentiation; Epithelial Cells; Lung Neoplasms; Mutation; Organoids; Precancerous Conditions; Proto-Oncogene Proteins p21(ras); Survival Rate; Tobacco Products
PubMed: 38418883
DOI: 10.1038/s41586-024-07113-9 -
Archives of Pathology & Laboratory... Feb 2024Macroscopic precursor lesions of the pancreas represent a complex clinical management problem. Molecular characterization of pancreatic cysts has helped to confirm and...
CONTEXT.—
Macroscopic precursor lesions of the pancreas represent a complex clinical management problem. Molecular characterization of pancreatic cysts has helped to confirm and refine clinical and pathologic classifications of these lesions, inform our understanding of tumorigenesis in the pancreas, and provide opportunities for preoperative diagnosis.
OBJECTIVE.—
To review the pathologic classification of macroscopic cystic lesions of the pancreas: intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), intraductal oncocytic papillary neoplasms (IOPNs), and intraductal tubulopapillary neoplasms (ITPNs), and to describe our current state of understanding of their molecular underpinnings, relationship to invasive carcinomas, and implications for diagnosis and prognostication.
DATA SOURCES.—
We assessed the current primary literature and current World Health Organization Classification of Digestive System Tumours.
CONCLUSIONS.—
Macroscopic cystic lesions of the pancreas are morphologically and molecularly diverse. IPMNs and MCNs share mucinous cytoplasm with papillae. MCNs are defined by ovarian-type stroma. IOPNs have granular eosinophilic cytoplasm, prominent nucleoli, and complex, arborizing papillae. ITPNs demonstrate complex, back-to-back tubules and anastomosing papillae and lack prominent intracellular mucin. IPMNs and MCNs are characterized by driver mutations in KRAS/GNAS (IPMNs) and KRAS (MCNs), with later driver events in RNF43, CDKN2A, SMAD4, and TP53. In contrast, IOPNs and ITPNs have recurrent rearrangements in PRKACA/PRKACB and MAPK-associated genes, respectively. The recurrent alterations described in cysts provide an opportunity for diagnosis using aspirated cyst fluid. Molecular characterization of IPMNs shows a striking spatial and mutational heterogeneity, challenging traditional models of neoplastic development and creating challenges to interpretation of cyst fluid sequencing results.
PubMed: 38386006
DOI: 10.5858/arpa.2023-0358-RA -
Asian Journal of Surgery Jun 2024
Topics: Humans; Female; Kidney Neoplasms; Adenoma, Oxyphilic; Adult; Carcinoma, Renal Cell; Nephrectomy; Tomography, X-Ray Computed
PubMed: 38383182
DOI: 10.1016/j.asjsur.2024.02.028 -
Trends in Cancer May 2024Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their... (Review)
Review
Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their identification can inform clinical management by enabling precision oncology, as fusions involving BRAF, FGFR2, RET, NTRK, NRG1, and ALK represent actionable targets in KRAS-WT cancers, and serve diagnostic purposes since fusions involving PRKACA/B represent the diagnostic hallmark of intraductal oncocytic papillary neoplasms (IOPNs). Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Oncogene Proteins, Fusion; Biomarkers, Tumor; Receptor, trkA; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins B-raf; Receptor, Fibroblast Growth Factor, Type 2; Neuregulin-1; Anaplastic Lymphoma Kinase; Gene Fusion
PubMed: 38378317
DOI: 10.1016/j.trecan.2024.01.009 -
Laryngoscope Investigative... Feb 2024To evaluate the clinical and prognostic behaviors of sinonasal papillomas.
OBJECTIVES
To evaluate the clinical and prognostic behaviors of sinonasal papillomas.
METHODS
Patients diagnosed with sinonasal papilloma were reviewed between 2001 and 2016 at a tertiary rhinology practice. Using pathology-specific electronic medical record software, patients diagnosed with sinonasal papilloma were identified. Four subcategories of this lesion were identified: inverting (IP), exophytic (EP) oncocytic (OP) and inverting + exophytic (IP + EP) papillomas.
RESULTS
A total of 107 patients were identified with unique sinonasal papilloma diagnoses. Of these, the majority were diagnosed with IP (87, 81.3%). The subpopulation of patients co-diagnosed with IP and EP (IP + EP) was unique with respect to clinical presentation and prognosis relative to both the IP and EP alone populations. IP + EP patients (5, 4.7%) were older with an average age of 75.25 years compared to 45 (EP) and 55.26 (IP), < .0001. IP + EP patients more often presented with epistaxis (60%) compared to 33.3% (EP) and 4.6% (IP). Finally, all IP + EP patients had at least one recurrence of their disease, compared to 33.3% (EP) and 28.5% (IP).
CONCLUSIONS
Each histopathologic subtype of sinonasal papilloma has unique clinical characteristics and recurrence rates after surgical resection. The subpopulation of patients diagnosed with IP + EP tends to be older, more likely to present with epistaxis, and more likely to recur. Additional investigation and analysis of this subpopulation is warranted.
LEVEL OF EVIDENCE
4.
PubMed: 38362195
DOI: 10.1002/lio2.1191 -
Surgical Case Reports Feb 2024Intraductal oncocytic papillary neoplasm (IOPN), previously classified as a subtype of intraductal papillary mucinous neoplasm (IPMN), has been described as an...
BACKGROUND
Intraductal oncocytic papillary neoplasm (IOPN), previously classified as a subtype of intraductal papillary mucinous neoplasm (IPMN), has been described as an independent disease by the WHO since 2019. IOPN is a rare tumor, with few reported cases. Herein, we report a case of resected non-invasive IOPN that formed a lesion protruding toward the duodenum from the accessory papilla.
CASE PRESENTATION
An 80-year-old woman was referred to our hospital because of a giant mass in the pancreatic head detected on abdominal contrast-enhanced computed tomography (CT) performed for a close examination of a mass in the right breast. CT revealed a 90-mm-sized tumor with a mixture of solid and cystic components, with contrast enhancement in the pancreatic head, and a dilated main pancreatic duct. Esophagogastroduodenoscopy revealed a semi-circumferential papillary tumor protruding toward the duodenal lumen, which did not protrude from the papilla of Vater. Transpapillary biopsy led to a preoperative diagnosis of IPMN with an associated invasive carcinoma. As there were no distant metastasis, open subtotal stomach-preserving pancreaticoduodenectomy was performed. Analysis of the surgical specimen and histopathological examination revealed that the tumor was an IOPN that protruded toward the duodenal mucosa from the accessory papilla while replacing the duodenal mucosa with no obvious stromal invasion.
CONCLUSION
IOPN is a rare and poorly recognized tumor with few reported cases. There have been no reports describing IOPN forming a protruding lesion toward the duodenum from the accessory papilla. Therefore, further accumulation of cases such as this one is important to advance the study of IOPN.
PubMed: 38358457
DOI: 10.1186/s40792-024-01841-w -
Journal For Immunotherapy of Cancer Feb 2024In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We... (Randomized Controlled Trial)
Randomized Controlled Trial
Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.
BACKGROUND
In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy.
METHODS
Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting.
RESULTS
With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed.
CONCLUSIONS
In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.
Topics: Adult; Humans; Nivolumab; Carcinoma, Non-Small-Cell Lung; Ipilimumab; B7-H1 Antigen; Treatment Switching; Lung Neoplasms; Neoplasm Recurrence, Local; Carcinoma, Squamous Cell
PubMed: 38346853
DOI: 10.1136/jitc-2023-008189