Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. ...This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). Methods We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 400 mg/m2 , and bolus fluorouracil 400 mg/m2 , followed by 2400 mg/m2 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01413022. Results Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5–89·0) in the FOLFIRINOX alone group and 77·0 days (70·0–90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. Interpretation CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Funding Washington University–Pfizer Biomedical Collaborative.
Abstract
Background
N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity.
Methods
Bladder ...cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate Cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan–Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated.
Results
Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan–Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib.
Conclusions
An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.
High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups ...aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.
Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.
For all registered patients at a median follow-up of 54 months (interquartile range: 38–73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval CI: 57–61%) and 54% (95% CI: 52–56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio HR = 2.34, 95% CI: 1.95–2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38–2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10–2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33–0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52–0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77–81%) and 71% (95% CI: 68–73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76–2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.
In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
•Osteosarcoma is a rare disease, and treatment can only improve with international collaboration.•We have assembled prospectively collected data from treatments of all the patients in the intercontinental European and American Osteosarcoma Study-1 protocol.•These consistently treated patients provided a strong data set for reporting survival outcomes and reporting on prognostic factors.•The trial reaffirms known prognostic factors, and the most adverse factors were metastases and tumours in the axial skeleton.•Owing to the large numbers of patients registered, light is shed on some additional factors to be considered. Around seven in ten patients were still alive five years after diagnosis.
About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ ...hybridization. This low HER2 expression is a promising new target for antibody-drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC).
The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included.
As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74-1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68-1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients.
Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.
Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC ...and its influence on the design of effective cancer immunotherapeutics.
We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays.
In-depth interrogation of the immune landscapes showed that regulatory T cells (T
) and CD8
resident memory T cells (T
) were enriched in HBV-related HCC, whereas Tim-3
CD8
T cells and CD244
natural killer cells were enriched in non-viral-related HCC. NGS of isolated T
and T
from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. T
and T
from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1
T
could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that T
and T
contributed to overall patient survival: T
were associated with a poor prognosis and T
were associated with a good prognosis in HCC.
We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics.
Systemic treatment for hepatocellular carcinoma (HCC) has been boosted by the incorporation of new agents after many negative phase III trials in the decade since the approval of sorafenib. Sorafenib ...introduced the concept that targeting specific hallmarks of hepatocarcinogenesis could modify the dismal prognosis of this disease, with the drug remaining a cornerstone in the upfront therapy for advanced HCC. The design of clinical trials in this malignancy is complicated by important obstacles related to patient selection, prognostic assessment and the need for endpoints that correlate with improvement in survival outcomes. In addition, the currently used criteria to determine treatment response or progression might prevent physicians from making appropriate clinical judgements and interpreting evidence arising from trials. In this Review, we discuss the advances in systemic therapy for HCC and critically review trial designs in HCC. Although novel therapies, such as new targeted agents and immunotherapies, are being rapidly incorporated, it is paramount to design future clinical trials based on the lessons learned from past failures and successes.
Lung squamous cell carcinoma (LUSC) is associated with poor clinical prognosis and lacks available targeted therapy. Novel molecules are urgently required for the diagnosis and prognosis of LUSC. ...Here, we conducted our data mining analysis for LUSC by integrating the differentially expressed genes acquired from Gene Expression Omnibus (GEO) database by comparing tumor tissues versus normal tissues (GSE8569, GSE21933, GSE33479, GSE33532, GSE40275, GSE62113, GSE74706) into The Cancer Genome Atlas (TCGA) database which includes 502 tumors and 49 adjacent non-tumor lung tissues. We identified intersections of 129 genes (91 up-regulated and 38 down-regulated) between GEO data and TCGA data. Based on these genes, we conducted our downstream analysis including functional enrichment analysis, protein-protein interaction, competing endogenous RNA (ceRNA) network and survival analysis. This study may provide more insight into the transcriptomic and functional features of LUSC through integrative analysis of GEO and TCGA data and suggests therapeutic targets and biomarkers for LUSC.
Breast cancer is the most common malignancy in women worldwide. Metastasis is the leading cause of high mortality in most cancers. Although predicting the early stage of breast cancer before ...metastasis can increase the survival rate, breast cancer is often discovered or diagnosed after metastasis has occurred. In general, breast cancer has a poor prognosis because it starts as a local disease and can spread to lymph nodes or distant organs, contributing to a significant impediment in breast cancer treatment. Metastatic breast cancer cells acquire aggressive characteristics from the tumor microenvironment (TME) through several mechanisms including epithelial–mesenchymal transition (EMT) and epigenetic regulation. Therefore, understanding the nature and mechanism of breast cancer metastasis can facilitate the development of targeted therapeutics focused on metastasis. This review discusses the mechanisms leading to metastasis and the current therapies to improve the early diagnosis and prognosis in patients with metastatic breast cancer.
This study aimed to establish and validate machine learning models for prognosis prediction in endodontic microsurgery, avoiding treatment failure and supporting clinical decision-making.
A total of ...234 teeth from 178 patients were included in this study. We developed gradient boosting machine (GBM) and random forest (RF) models. For each model, 80% of the data were randomly selected for the training set and the remaining 20% were used as the test set. A stratified 5-fold cross-validation approach was used in model training and testing. Correlation analysis and importance ranking were conducted for feature selection. The predictive accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), F1 score, and the area under the curve (AUC) of receiver operating characteristic (ROC) curves were calculated to evaluate the predictive performance.
There were eight important predictors, including tooth type, lesion size, type of bone defect, root filling density, root filling length, apical extension of post, age, and sex. For the GBM model, the predictive accuracy was 0.80, with a sensitivity of 0.92, specificity of 0.71, PPV of 0.71, NPV of 0.92, F1 of 0.80, and AUC of 0.88. For the RF model, the accuracy was 0.80, with a sensitivity of 0.85, specificity of 0.76, PPV of 0.73, NPV of 0.87, F1 of 0.79, and AUC of 0.83.
The trained models were developed by eight common variables, showing the potential ability to predict the prognosis of endodontic microsurgery. The GBM model outperformed the RF model slightly on our dataset.
Clinicians can use machine learning models for preoperative analysis in endodontic microsurgery. The models are expected to improve the efficiency of clinical decision-making and assist in clinician-patient communication.
Objectives: This study aims to determine the association of neutrophil-lymphocyte ratio (NLR) with sequential organ failure assessment (SOFA) score, ventilator use, duration of intensive care unit ...(ICU) stay, and mortality among patients with sepsis. Methods: This prospective observational study included 220 patients with sepsis admitted to the ICU. Details such as age, gender, comorbidities, complaints, SOFA score, diagnosis, and outcomes were collected. Routine investigations included complete blood count, C-reactive protein, and procalcitonin. NLR was derived using the Beckman Coulter DXH-800 Hematology Analyser. A cutoff of 9.11 was taken as high NLR. Patients were followed up till 28 days after treatment. The outcomes studied included 28-day mortality and ICU stay. Results: The mean SOFA score were 7.07 ± 2.56. Based on NLR cutoffs, 146 (66.36%) patients had high NLR while 74 (33.64%) cases had normal or low NLR. SOFA score showed no significant association with high NLR ( P = 0.62). Ventilator was used in 118 (53.6%) cases with median of 3.5 days’ duration. The overall ICU stay was 5.6 ± 4.9 days. Mortality was seen in 46 (20.9%) cases. Compared to those with normal NLR, patients with high NLR had significantly more ventilator use (60.9% vs. 39.1%, P = 0.0027) and mortality (30.14% vs. 2.7%, P = 0.0004). The duration of ventilator use and ICU stay was statistically comparable. Conclusion: High NLR shows a significant association with adverse outcomes of sepsis patients in terms of ventilator use and mortality. Since it is cheap and easy to use, it can be applied in more basic settings while monitoring sepsis patients.
PDF
