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Modern Pathology : An Official Journal... Nov 2021For neoadjuvant therapy in patients with non-small cell lung cancer, the major pathologic response of primary tumors may be an assessable and reliable surrogate measure...
For neoadjuvant therapy in patients with non-small cell lung cancer, the major pathologic response of primary tumors may be an assessable and reliable surrogate measure of survival. Few studies have examined the pathologic evaluation of metastatic lymph node responses and their prognostic significance. This retrospective study enrolled 336 patients with non-small cell lung cancer (squamous cell carcinoma, n = 216; adenocarcinoma, n = 120) treated with neoadjuvant therapy including chemotherapy (n = 316) and targeted therapy (adenocarcinoma, n = 20). The treatment response of the primary tumor and lymph node metastases (LNM) were pathologically assessed according to the multidisciplinary recommendations of the International Association for the Study of Lung Cancer. The relationship of overall survival (OS) and disease-free survival (DFS) with the responses of the primary tumor or LNM was analyzed. The optimal cutoff value of the residual viable tumor (%RVT) of the primary tumor was 12% for both OS (P < 0.001) and DFS (P < 0.001). The pathologic assessment identified LNM in 208 patients. The optimal %RVT cutoff value in LNM was 8% for both OS (P = 0.003) and DFS (P < 0.001). The Spearman's rank correlation coefficient between primary tumors and corresponding LNM was 0.487 for %RVT (P < 0.001), which indicated a positive correlation. On multivariable analysis, an RVT of the primary tumor ≤12% was an independent prognostic factor for improved OS (P = 0.024), whereas an RVT of LNM ≤ 8% was an independent prognostic factor for increased DFS (P = 0.018). Furthermore, in the neoadjuvant chemotherapy group, the optimal %RVT cutoff values for OS in patients with squamous cell carcinoma and adenocarcinoma in the primary tumor were 12% and 58%, respectively. Considering its convenience and operability in clinical application, a 10% threshold RVT value can be used for prognostic evaluation of LNM and primary tumors of squamous cell carcinoma histology; further studies are needed to confirm the optimal cutoff value for primary tumors of adenocarcinoma.
Topics: Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Lung Neoplasms; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Retrospective Studies; Survival Rate
PubMed: 34253867
DOI: 10.1038/s41379-021-00871-1 -
Acta Neuropathologica Communications Aug 2023Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases....
Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases. Recently, we demonstrated a robust upregulation of type I interferon-stimulated genes in microglia and astrocytes following experimental traumatic brain injury (TBI). The specific molecular and cellular mechanisms by which IFN-I signaling impacts the neuroimmune response and neuropathology following TBI remains unknown. Using the lateral fluid percussion injury model (FPI) in adult male mice, we demonstrated that IFN α/β receptor (IFNAR) deficiency resulted in selective and sustained blockade of type I interferon-stimulated genes following TBI as well as decreased microgliosis and monocyte infiltration. Molecular alteration of reactive microglia also occurred with diminished expression of genes needed for MHC class I antigen processing and presentation following TBI. This was associated with decreased accumulation of cytotoxic T cells in the brain. The IFNAR-dependent modulation of the neuroimmune response was accompanied by protection from secondary neuronal death, white matter disruption, and neurobehavioral dysfunction. These data support further efforts to leverage the IFN-I pathway for novel, targeted therapy of TBI.
Topics: Male; Animals; Mice; Interferon Type I; Neuropathology; Brain Injuries, Traumatic; Brain; Antibodies
PubMed: 37596685
DOI: 10.1186/s40478-023-01635-5 -
JTO Clinical and Research Reports May 2022The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response... (Review)
Review
The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.
PubMed: 35498382
DOI: 10.1016/j.jtocrr.2022.100310 -
Clinical Cancer Research : An Official... Feb 2020Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term...
PURPOSE
Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed.
EXPERIMENTAL DESIGN
Hematoxylin and eosin-stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types.
RESULTS
Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non-small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features.
CONCLUSIONS
irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.
Topics: B7-H1 Antigen; Humans; Immunotherapy; Neoplasms; Pathology, Clinical; Programmed Cell Death 1 Receptor; Research Design; Response Evaluation Criteria in Solid Tumors; Treatment Outcome
PubMed: 31672770
DOI: 10.1158/1078-0432.CCR-19-2379 -
Cancers Dec 2022Background: The clinical course of complete pathologic response (cPR) in pancreatic cancer after neoadjuvant chemotherapy is not well known. The aim of this study was to...
Background: The clinical course of complete pathologic response (cPR) in pancreatic cancer after neoadjuvant chemotherapy is not well known. The aim of this study was to investigate the clinical course of patients according to pathological response, including cPR, who received only FOLIFIRNOX in advanced pancreatic cancer. Methods: Patients who underwent pancreatectomy after FOLFIRINOX for pancreatic ductal adenocarcinoma (PDAC) from 2017 to 2019 were retrospectively reviewed. cPR was defined as an absence of residual tumor on pathologic report. A nearly complete pathologic response (ncPR) was defined as a tumor confined to pancreas parenchyma, less than 1 cm without lymph-node metastasis. cPR and ncPR were assigned into a favorable pathologic response group (fPR). Kaplan−Meier method and Cox proportional hazard models were used for analysis. Results: Of a total 64 patients, 8 (12.5%) had a cPR and 8 (12.5%) had a ncPR. In the fPR group, median OS and DFS were superior to those of non-pathologic response group (more than 60 months vs. 38 months, p < 0.001; more than 42 months vs. 10 months, p < 0.001). On multivariable analyses, fPR and adjuvant therapy were independent prognostic factors for OS (HR: 0.12; 95% CI: 0.02−0.96, p = 0.05; HR: 0.26; 95% CI: 0.09−0.74, p = 0.01) and DFS (HR: 0.31; 95% CI: 0.12−0.86, p = 0.02; HR:0.31; 95% CI: 0.13−0.72, p = 0.01). Conclusions: pathologic response predicts survival after pancreatectomy following neoadjuvant FOLFIRINOX for pancreatic cancer, and adjuvant chemotherapy following neoadjuvant treatment might be beneficial for OS and DFS.
PubMed: 36612289
DOI: 10.3390/cancers15010294 -
Thoracic Cancer Nov 2022Immunotherapy has been proved to have a large effect on extensive-stage small cell lung cancer, but the role of immunotherapy in limited-stage small-cell lung cancer...
BACKGROUND
Immunotherapy has been proved to have a large effect on extensive-stage small cell lung cancer, but the role of immunotherapy in limited-stage small-cell lung cancer (LS-SCLC) is still unknown.
METHODS
A retrospective study of six patients with LS-SCLC who were treated with neoadjuvant chemoimmunotherapy (durvalumab plus etoposide combined with cisplatin) was performed. Patients were evaluated by the safety, feasibility and pathologic responses of neoadjuvant chemoimmunotherapy.
RESULTS
Neoadjuvant durvalumab combined chemotherapy was associated with few immediate adverse events and did not delay planned surgery. All patients achieved partial pathologic response (pPR) instead of major pathologic response, or pathologic complete response. No association was observed between programmed death-ligand 1 expression in tumor specimens and the pathologic response. However, tumors with high expression of immune cells such as CD4+ T cells, CD8+ T cells and FoxP3+ Tregs tended to have better pathologic responses than tumors with low expression of immune cells.
CONCLUSIONS
Neoadjuvant durvalumab combined chemotherapy could induce pPR with few side effects in resectable LS-SCLC. The immune cells in the tumor microenvironment might play an important role in neoadjuvant chemoimmunotherapy in resectable LS-SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Neoadjuvant Therapy; Lung Neoplasms; Retrospective Studies; Immunotherapy; Tumor Microenvironment
PubMed: 36208136
DOI: 10.1111/1759-7714.14679 -
Platelets Apr 2021Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce... (Review)
Review
Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications.
Topics: Blood Platelets; Female; Humans; Male; Platelet Count; Wounds and Injuries
PubMed: 31986948
DOI: 10.1080/09537104.2020.1718633 -
Journal of Personalized Medicine Feb 2021Despite research into the epidemiological link between exposure to particulate matter (PM) and renal disorder, there is limited information available on the etiological... (Review)
Review
Despite research into the epidemiological link between exposure to particulate matter (PM) and renal disorder, there is limited information available on the etiological complexity and molecular mechanisms. Among the early responsive tissues to PM exposure, the mucosal barrier of the airway and alimentary tract may be a crucial source of pathologic mediators leading to inflammatory renal diseases, including chronic kidney disease (CKD). Given that harmful responses and products in mucosa exposed to PM may enter the circulation and cause adverse outcomes in the kidney, the aim of the present review was to address the impact of PM exposure on the mucosal barrier and the vicious feedback cycle in the mucosal environment. In addition to the PM-induced alteration of mucosal barrier integrity, the microbial community has a pivotal role in the xenobiotic metabolism and individual susceptibility to PM toxicity. The dysbiosis-induced deleterious metabolites of PM and nutrients are introduced systemically via a disrupted mucosal barrier, contributing to renal injuries and pathologic severity. In contrast, the progress of mucosa-associated renal disease is counteracted by endogenous protective responses in the mucosa. Along with direct elimination of the toxic mediators, modulators of the mucosal microbial community should provide a promising platform for mucosa-based personalized interventions against renal disorders caused by air pollution.
PubMed: 33670188
DOI: 10.3390/jpm11020118 -
Experimental Gerontology Apr 2023Low back pain (LBP) is one of the most common health problems in people's lives, which brings a massive burden to clinicians, and the leading cause of LBP is... (Review)
Review
Low back pain (LBP) is one of the most common health problems in people's lives, which brings a massive burden to clinicians, and the leading cause of LBP is intervertebral disc degeneration (IDD). IDD is mainly caused by factors such as aging, mechanical stress, and lack of nutrition. The pathological mechanism of IDD is very complex, involving inflammatory response, cell metabolism disorder, and so on. Unfortunately, in the current treatment of IDD, only relieving symptoms as the primary means of relieving a patient's pain cannot effectively inhibit or reverse the progression of IDD. Tumor necrosis factor-α (TNF-α) is a multifunctional pro-inflammatory factor involved in many diseases' pathological processes. With the in-depth study of the pathological mechanism of IDD, more and more evidence has shown that TNF-α is an essential activator of IDD, which is related to the metabolic disorder, inflammatory responses, apoptosis, and other pathological processes of extracellular dissociation in the intervertebral disc. Therefore, anti-TNF-α therapy is an effective therapeutic target for alleviating IDD, especially in inhibiting extracellular matrix degradation and reducing inflammatory responses. This article reviews the pathological role of TNF-α in IDD and the latest research progress of TNF-α inhibitors in treating IDD.
Topics: Humans; Intervertebral Disc Degeneration; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor Inhibitors; Intervertebral Disc
PubMed: 36758650
DOI: 10.1016/j.exger.2023.112119 -
Cancer Medicine Jun 2023Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes...
BACKGROUND
Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients.
METHODS
This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m on day 1 and 8, and cisplatin 70 mg/m on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0).
RESULTS
From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified.
CONCLUSIONS
Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.
Topics: Humans; Cisplatin; Gemcitabine; Neoadjuvant Therapy; Urinary Bladder Neoplasms; Deoxycytidine; Cystectomy; Muscles; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Invasiveness
PubMed: 37021811
DOI: 10.1002/cam4.5900