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Journal For Immunotherapy of Cancer Mar 2024Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic... (Randomized Controlled Trial)
Randomized Controlled Trial
Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial.
BACKGROUND
Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).
METHODS
CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed.
RESULTS
From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified.
CONCLUSIONS
The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted.
TRIAL REGISTRATION NUMBER
NCT03414983.
Topics: Humans; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Irinotecan; Nivolumab; Oxaliplatin; Rectal Neoplasms; Adolescent; Adult
PubMed: 38485190
DOI: 10.1136/jitc-2023-008409 -
Journal For Immunotherapy of Cancer Mar 2024Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study... (Randomized Controlled Trial)
Randomized Controlled Trial
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial.
BACKGROUND
Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics.
METHODS
Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm (median) vs ≥5 per mm), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present).
RESULTS
Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm and 0.57 (0.40 to 0.80) for ≥5 per mm; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS.
CONCLUSIONS
In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov, NCT03553836.
Topics: Humans; Adjuvants, Immunologic; Antibodies, Monoclonal, Humanized; Combined Modality Therapy; Melanoma; Skin Neoplasms; Adolescent; Adult
PubMed: 38485189
DOI: 10.1136/jitc-2023-007501 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Feb 2024Oncocytoma is a benign tumor of the salivary gland. Its incidence is very low and very seldom documen-ted in literature. Clear-cell dominant oncocytoma is even less... (Review)
Review
Oncocytoma is a benign tumor of the salivary gland. Its incidence is very low and very seldom documen-ted in literature. Clear-cell dominant oncocytoma is even less common. The tumor's clinical symptoms and imaging results are nonspecific, so distinguishing other salivary gland tumors (such as oncocytic carcinoma) from clear-cell renal carcinoma is difficult, possibly leading to misdiagnosis and maltreatment. Here, a case of clear-cell dominant oncocytoma was presented, and the relevant literature was evaluated to investigate the diagnosis and management of clear-cell dominant oncocytoma.
Topics: Humans; Parotid Gland; Adenoma, Oxyphilic; Salivary Gland Neoplasms; Diagnosis, Differential
PubMed: 38475961
DOI: 10.7518/hxkq.2024.2023185 -
Cancers Feb 2024Warthin's tumor is the second most frequent neoplasm next to pleomorphic adenoma in the salivary gland, mostly in the parotid gland. The epithelial cells constituting a... (Review)
Review
Warthin's tumor is the second most frequent neoplasm next to pleomorphic adenoma in the salivary gland, mostly in the parotid gland. The epithelial cells constituting a tumor are characterized by the presence of mitochondria that undergo structural and functional changes, resulting in the development of oncocytes. In addition to containing epithelial cells, Warthin's tumors contain abundant lymphocytes with lymph follicles (germinal centers) that are surrounded by epithelial cells. The pathogenesis of Warthin's tumor is not fully understood, and several hypotheses have been proposed. The risk factors for the development of Warthin's tumor, which predominantly occurs in males, include aging, smoking, and radiation exposure. Recently, it has been reported that chronic inflammation and aging cells promote the growth of Warthin's tumor. Several reports regarding the origin of the tumor have suggested that (1) Warthin's tumor is an IgG4-related disease, (2) epithelial cells that compose Warthin's tumor accumulate mitochondria, and (3) Warthin's tumor is a metaplastic lesion in the lymph nodes. It is possible that the pathogenesis of Warthin's tumor includes mitochondrial metabolic abnormalities, accumulation of aged cells, chronic inflammation, and senescence-associated secretory phenotype (SASP). In this short review, we propose that DNA damage, metabolic dysfunction of mitochondria, senescent cells, SASP, human papillomavirus, and IgG4 may be involved in the development of Warthin's tumor.
PubMed: 38473274
DOI: 10.3390/cancers16050912 -
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 -
Modern Pathology : An Official Journal... May 2024Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health...
Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.
Topics: Humans; Kidney Neoplasms; Carcinoma, Renal Cell; Female; Male; Middle Aged; Biomarkers, Tumor; Neural Cell Adhesion Molecule L1; Aged; Adult; Adenoma, Oxyphilic; Diagnosis, Differential; Aged, 80 and over; Immunohistochemistry; Neoplasm Grading; Mutation
PubMed: 38460672
DOI: 10.1016/j.modpat.2024.100467 -
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 -
Head and Neck Pathology Mar 2024Despite the increasing recognition of PD-L1 as predictor of immunotherapeutic response in various malignancies, its role and prognostic significance in thyroid cancer...
BACKGROUND
Despite the increasing recognition of PD-L1 as predictor of immunotherapeutic response in various malignancies, its role and prognostic significance in thyroid cancer remain underexplored and subject to debate. This study begins to address this gap by comprehensively analyzing PD-L1 expression in papillary thyroid carcinoma (PTC) and investigating its correlation with key clinicopathological variables.
METHODS
We conducted immunohistochemistry (IHC) to assess PD-L1 expression in whole-tissue sections from 121 primary papillary thyroid carcinoma (PTC) cases. We then analyzed the correlations between PD-L1 expression and various clinicopathological variables.
RESULTS
PD-L1 expression was detected in 33.1% of papillary thyroid carcinomas (PTCs), predominantly exhibiting weak to moderate intensity. Notably, this study found no significant correlation between PD-L1 expression and various clinicopathological variables. The lack of association with traditional factors such as age, sex, histological subtype, and tumor size suggests the complex and multifaceted nature of PD-L1 regulation in PTC. Multivariate logistic regression analysis identified chronic lymphocytic thyroiditis with oncocytic metaplasia as the sole independent predictor of PD-L1 expression (P = 0.014), underlining the potential influence of the tumor microenvironment on immune checkpoint expression in PTC.
CONCLUSIONS
Our study underscores the intricate interplay between chronic lymphocytic thyroiditis with oncocytic metaplasia and PD-L1 expression in papillary thyroid carcinoma. The observed link suggests a potential avenue for therapeutic intervention using anti-PD-1/PD-L1 therapies in surgery-refractory PTC. Understanding the dynamics of immune checkpoint regulation in the context of the tumor microenvironment is crucial for devising effective treatment strategies. Future research endeavors should delve deeper into the molecular mechanisms underlying this interaction and explore its implications for patient outcomes. As the field of immunotherapy continues to evolve, our findings contribute valuable insights into the complex immunological landscape of thyroid cancer.
Topics: Humans; Thyroid Cancer, Papillary; Hashimoto Disease; B7-H1 Antigen; Thyroid Neoplasms; Metaplasia; Tumor Microenvironment
PubMed: 38457034
DOI: 10.1007/s12105-024-01618-5 -
Pathology International Apr 2024Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described indolent entity with distinct features and its recognition from other...
Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described indolent entity with distinct features and its recognition from other oncocytic/eosinophilic papillary renal cell carcinoma (ePRCC) has important prognostic implications. ABCC2, a renal drug transporter, is overexpressed in aggressive PRCCs. In this study, we compared the clinicopathological parameters and the biological ABCC2 expression between PRNRP and ePRCC. PRNRP (n = 8) and ePRCC (n = 21) cases were selected from resection specimens and corresponding clinicopathological data were collected. ABCC2 immunohistochemical (IHC) staining was performed and ABCC2 staining patterns were classified as negative, cytoplasmic, and brush-border. RNA in-situ hybridization (ISH) was used to assess ABCC2 transcript levels. All eight PRNRP cases had weak cytoplasmic ABCC2 IHC reactivity; however, they showed no detectable ABCC2 transcripts on RNA ISH. In comparison, 76% (16/21) of ePRCCs showed ABCC2 IHC brush-border expression and significantly higher ABCC2 RNA ISH transcript levels (p < 0.001). Additionally, the ePRCC group showed a significantly larger tumor size (p = 0.004), higher WHO/ISUP grade (p < 0.001), and stage (p = 0.044). None of the PRNRP cases showed disease progression, while 9.5% (2/21) ePRCCs had disease progression. PRNRP is clinically and biologically distinct from ePRCC. Hence, it is crucial to differentiate between these two entities, particularly in needle core biopsies.
Topics: Humans; Carcinoma, Renal Cell; Immunohistochemistry; Biomarkers, Tumor; Kidney Neoplasms; Disease Progression; RNA
PubMed: 38456605
DOI: 10.1111/pin.13417 -
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