Prolonged Disease-free Survival Research Articles

Exploring the Heterogeneity of Response to Blinatumomab in High-Risk Philadelphia-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: An Analysis from the QUEST Sub-Study of the Graall-2014/B Trial

Introduction. Adults with Philadelphia (Ph)-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) benefit from blinatumomab (BLIN) in first-line consolidation. However, the magnitude of this benefit according to baseline patient and disease characteristics remains largely unexplored. In the GRAALL-2014/B QUEST sub-study, patients with high-risk (HR) features (i.e. post-induction MRD1 ≥10 -4, IKZF1 intragenic deletion, or KMT2A rearrangement) received BLIN during consolidation. Patients eligible to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR) (i.e. those with late CR, or post-induction MRD1 ≥10 -3, or post-consolidation MRD2 ≥10 -4) received only one BLIN cycle before transplant. A control cohort was established from patients enrolled in the same protocol who exhibited the same HR criteria but did not receive BLIN in first CR. The objective of this analysis was to identify patient- and disease-related factors associated with response to BLIN, and to understand how BLIN influences the outcome after allo-HSCT. Method. Between December 2015 and December 2020, the GRAALL-2014/B trial included 489 patients with Ph-negative BCP-ALL. Among these patients, 266 presented with HR features as defined above and 95 (including 94 evaluable patients) were included in QUEST between October 2018 and December 2020. A control group of 104 patients treated in the same trial, meeting the QUEST eligibility criteria, but not included in QUEST and not exposed to BLIN in CR1 was defined. Results have been presented last year (Boissel et al. ASH Meeting 2022). Here, we investigated which factors were associated with the benefit of BLIN in terms of MRD3 response (1 st post-BLIN MRD) and disease-free-survival (DFS). The most frequently observed genetic entities were included in the analysis (Ph-like, KMT2A-r, low hypodiploidy/near triploidy [HoTr], DUX4-r, ZNF384-r). Results. Patients from the QUEST cohort had a higher chance to be MRD3-negative (<10 -4) when compared to the control cohort (OR, 2.8; 95%CI, 1.3-6.2; p=0.011). Among them, younger patients (<45y), patients with WBC<30 G/L, with poor prednisone response, with IKZF1 deletion or with Ph-like disease had a significantly higher chance to be MRD3-negative after BLIN than after chemotherapy. Among genetic entities, ORs ranged from 1.2 for KMT2A-r to 5.3 for Ph-like BCP-ALL (Figure A). Due to a reduced risk of relapse, patients had a significantly prolonged DFS after BLIN (HR, 0.49; 95%CI, 0.31-0.78; p=0.002), whatever their age (< vs ≥45y), WBC at diagnosis (< vs ≥30 G/L), prednisone response, and MRD1 (<10 -4vs ≥10 -4) (Figure B). Among genetic entities, HR for DFS ranged from 0.21 for DUX4-r to 1.38 for HoTr with none of these differences that reached significance. Patients with IKZF1 deletion had the most significant benefit from BLIN on DFS (HR, 0.21; 95%CI, 0.08-0.52; p=0.001) with a significant interaction between IKZF1 status and the use of BLIN (p=0.011). Patients who received allo-HSCT had a higher chance to be MRD negative before transplant when treated with BLIN (OR, 4.0; 95%CI, 1.4-11.7; p=0.011), however this did not translate into a longer DFS (HR, 0.79; 95%CI, 0.39-1.60). In addition, prior transplant MRD level had a higher impact on post-transplant DFS in the patients exposed to BLIN (HR, 0.28; 95%CI, 0.10-0.79; p=0.017) than in those treated with chemotherapy (HR, 0.74; 95%CI, 0.24-2.27; p=0.60). Conclusion. In adult patients with Ph-negative BCP-ALL who experience an overall benefit of BLIN in consolidation, the present study reveals a heterogeneous landscape of response among genetic entities. Larger prospective studies should further explore this heterogeneity to refine implementation of BLIN in frontline setting.

Development of a nomogram for predicting survival of breast cancer patients with neoadjuvant chemotherapy: a dynamic analysis for systemic inflammation response index.

The systemic inflammation response index (SIRI) has been reported to associate with survival outcomes in breast cancer patients. However, the effects of baseline SIRI and SIRI change after neoadjuvant chemotherapy (NACT) have not been thoroughly investigated. This study aimed to evaluate the role of baseline SIRI and SIRI change after NACT in predicting survival outcomes, and establish a nomogram based on SIRI. A total of 260 patients diagnosed with breast cancer who received NACT between January 2014 and December 2018 at our hospital were included. The clinical data were retrospectively collected from the medical records management system. The associations between clinicopathological factors and baseline SIRI, pathological complete response (pCR) were analyzed by Student's t-test, Chi-squared test, or Fisher's exact test. The association between clinicopathological factors and disease-free survival (DFS) was evaluated by univariate and multivariate Cox regression analyses. Patients with a tumor-node-metastasis (TNM) stage of I, II, and III were 1.9%, 20.0%, and 78.1% respectively. The median follow-up time was 40 months, and 74 (28.5%) patients had cancer recurrence during the follow-up. Both in the univariate and multivariate analysis, Ki-67, pCR, and baseline SIRI were independent factors associated with DFS. Patients with low baseline SIRI had prolonged DFS compared with those with high baseline SIRI [≤1.6×109 vs. >1.6×109, hazard ratio (HR) =0.545, P=0.028]. In addition, SIRI change after NACT was also an independent factor associated with DFS, and patients with minor SIRI change had longer DFS than patients with major SIRI change (>50% or <-30% vs. ≤50% and ≥-30%, HR =1.721, P=0.037). Nomograms were established based on Ki-67, pCR, and baseline SIRI or SIRI change after NACT with a concordance index of 0.665 and 0.663 respectively, and the nomogram provided a convenient tool for predicting the probability of DFS. The baseline SIRI and SIRI change after NACT could act as potential biomarkers for predicting survival outcomes in breast cancer. Besides, the nomogram with SIRI is an economic and convenient tool for predicting DFS. Larger prospective studies are needed to verify the results.

Cost-Effectiveness Analysis of Pembrolizumab as an Adjuvant Treatment of Renal Cell Carcinoma Post-nephrectomy in the United States.

Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective. A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses. Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations. Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold.

B-199 Performance of the MasSpec Pen for Intraoperative Margin Evaluation During Breast Conserving Surgeries

Abstract Background Breast cancer is the second leading cause of cancer deaths among females worldwide. Surgical resection is the most common treatment option for women diagnosed with breast cancers. Many women with in situ disease or early invasive breast cancer are candidates for breast conserving surgery (BCS), which involves removing the lesion of interest and preserving the rest of the breast. One of the greatest challenges a breast cancer surgeon faces is to achieve negative margins while optimizing aesthetic outcomes. Negative margins are highly desirable as they offer the greatest potential for prolonged disease-free survival. Accurate intraoperative surgical margin evaluation is therefore critical during BSC. Molecular technologies offer the opportunity to incorporate cancer-specific biomarkers into clinical decision-making for improved cancer detection. Our team has reported the development of an innovative handheld mass spectrometry (MS) probe, the MasSpec Pen (MSPen), for rapid and gentle molecular analysis of human tissues, including breast cancer tissues. The MSPen uses water to gently extract molecules from tissues upon contact, which are then analyzed by MS and statistical classifiers to provide a predictive classification within seconds. Here, we evaluate the performance of the MSPen for intraoperative detection of breast cancer. Methods The MSPen coupled to an Orbitrap Exploris 120 (Thermo Scientific) is being used to analyze both normal breast and invasive lobular carcinoma (ILC) banked tissues. Tissue samples are first thawed prior to analysis. After analysis, the region analyzed is demarcated, and the samples snap-frozen, sectioned, H&amp;E stained, following evaluation by a pathologist. We will then apply the least absolute shrinkage and selector operator (lasso) method to build classification models for distinguishing normal breast and ILC using the histologically validated mass spectra. The MSPen system is also implemented in the operating room for testing within surgical workflow. Analyses will be carried out during BCS surgeries for patients with ILC. The ILC classifier generated from banked tissues will be used to predict on data obtained from the intraoperative analyses and validated against final histopathological reports. Results To date, we have analyzed 213 banked human breast tissues using the MSPen, including healthy breast (n = 79), invasive ductal carcinoma (IDC) (n = 64), healthy lymph nodes (n = 26), and lymph nodes with metastatic IDC (n = 44). The rich mass spectral data obtained from breast tissues showed high relative abundance of various metabolites and lipid species that have been previously described as potentially diagnostic of breast cancer. Using this data, we built classifiers that discriminate cancer and normal breast tissues with high accuracy (overall 94%) for primary breast IDC. In a pilot clinical study, we demonstrated feasibility for ex vivo and in vivo tissue analysis using the MSPen platform during 29 breast surgeries. We are currently expanding our study to detect ILC using banked tissues and in patient tissues intraoperatively. Conclusion Our study in breast cancer provides evidence that the MSPen enables molecular-based diagnosis of IDC tissues using excised specimens and in in vivo and ex vivo analysis performed by surgeons intraoperatively. Current effort including ILC is expected to show similar capabilities for patients with ILC.

C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration.

C-X-C motif chemokine ligand 9 (CXCL9) plays an important role in antitumor immunity through the recruitment, proliferation, and activation of immune cells (IC). Here, we evaluated the expression patterns of CXCL9 and programmed death-ligand 1 (PD-L1) in a cohort of 268 patients with triple-negative breast cancer (TNBC) by tissue microarray (TMA). The correlations between CXCL9 expression in ICs or tumor cells (TC) and clinicopathologic parameters, PD-L1 expression, tumor-infiltrating lymphocytes (TIL) and survival were analyzed in this cohort (n = 268). In addition, we analyzed a TNBC dataset (n = 138) from The Cancer Genome Atlas (TCGA) to identify correlation between CXCL9 expression and other immune gene expression, immune infiltration, and prognosis. The results of the TMA cohort (n = 268) showed that CXCL9 was expressed in 80.6% cases, with elevated expression levels in ICs relative to in TCs (median: 1% vs. 0%). CXCL9 expressed in ≥1% of ICs was categorized as the CXCL9-IC-positive group. CXCL9-IC expression was strongly and positively correlated with the PD-L1 expression, CD3+ TILs, CD4+ TILs, CD8+ TILs, and CD19+ TILs (all P < 0.0001). Survival analyses showed that the CXCL9-IC-positive group demonstrated prolonged disease-free survival (P = 0.038) and overall survival (P = 0.023) compared with the negative group. The analyses from TCGA cohort (n = 138) showed that elevated CXCL9 expression correlated with increased infiltration of B cells, macrophages, natural killer cells, monocytes and increased expression of immune checkpoint molecules and other CXCL family members, including CXCL10 and CXCL11. These findings confirm the regulatory role of CXCL9 in antitumor immunity and suggest a potential role in treatments involving immune checkpoint blockade.

Comprehensive pan-cancer analysis of expression profiles and prognostic significance for NUMB and NUMBL in human tumors.

NUMB has been initially identified as a critical cell fate determinant that modulates cell differentiation via asymmetrical partitioning during mitosis, including tumor cells. However, it remains absent that a systematic assessment of the mechanisms underlying NUMB and its homologous protein NUMBLIKE (NUMBL) involvement in cancer. This study aimed to investigate the prognostic significance for NUMB and NUMBL in pan-cancer. In this study, using the online databases TIMER2.0, gene expression profiling interactive analysis, cBioPortal, the University of ALabama at Birmingham CANcer data analysis Portal, SearchTool for the Retrieval of Interacting Genes/Proteins, and R software, we focused on the relevance between NUMB/NUMBL and oncogenesis, progression, mutation, phosphorylation, function and prognosis. This study demonstrated that abnormal expression of NUMB and NUMBL were found to be significantly associated with clinicopathologic stages and the prognosis of survival. Besides, genetic alternations of NUMB and NUMBL focused on uterine corpus endometrial carcinoma, and higher genetic mutations of NUMBL were correlated with more prolonged overall survival and disease-free survival in different cancers. Moreover, S438 locus of NUMB peptide fragment was frequently phosphorylated in 4 cancer types and relevant to its phosphorylation sites. Furthermore, endocytosis processing and neurogenesis regulation were involved in the functional mechanisms of NUMB and NUMBL separately. Additionally, the pathway enrichment suggested that NUMB was implicated in Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways, while MAPK, Hippo, Rap1, mTOR, and Notch pathways were related to the functions of NUMBL. This study highlights the predictive roles of NUMB and NUMBL in pan-cancer, suggesting NUMB and NUMBL might be served as potential biomarkers for diagnosis and prognosis in various malignant tumors.

Expression of four cancer-testis antigens in TNBC indicating potential universal immunotherapeutic targets

ObjectiveImmunotherapy is an attractive treatment for breast cancer. Cancer-testis antigens (CTAs) are potential targets for immunotherapy for their restricted expression. Here, we investigate the expression of CTAs in breast cancer and their value for prognosis. So as to hunt for a potential panel of CTAs for universal immunotherapeutic targets.Material and methodsA total of 137 breast cancer tissue specimens including 51 triple-negative breast cancer (TNBC) were assessed for MAGE-A4, MAGEA1, NY-ESO-1, KK-LC-1 and PRAME expression by immunohistochemistry. The expression of PD-L1 and TILs was also calculated and correlated with the five CTAs. Clinical data were collected to evaluate the CTA’s value for prognosis. Data from the K-M plotter were used as a validation cohort.ResultsThe expression of MAGE-A4, NY-ESO-1 and KK-LC-1 in TNBC was significantly higher than in non-TNBC (P = 0.012, P = 0.005, P < 0.001 respectively). 76.47% of TNBC expressed at least one of the five CTAs. Patients with positive expression of either MAGE-A4 or PRAME had a significantly extended disease-free survival (DFS). Data from the Kaplan–Meier plotter confirm our findings.ConclusionsMAGE-A4, NY-ESO-1, PRAME and KK-LC-1 are overexpressed in breast cancer, especially in TNBC. Positive expression of MAGE-A4 or PARME may be associated with prolonged DFS. A panel of CTAs is attractive universal targets for immunotherapy.

Brief report: risk stratification following curative therapy for stage I NSCLC.

Surveillance with computed tomography (CT) imaging following curative treatment of stage I non-small cell lung cancer (NSCLC) is important to identify recurrence or second primary lung cancers (SPLC). The pattern and risks of recurrence following curative therapy and optimal duration of surveillance scans remain unknown. The objective of our study is to assess the pattern of recurrence and development of SPLC to risk stratify patients with stage I NSCLC following curative therapy. We identified 261 patients who received curative therapy for stage I NSCLC at Mayo Clinic Florida. Data was collected on clinical and demographic features including gender, smoking history, stage, treatment, histologic subtype, and tumor grade. Kaplan-Meier method was used to evaluate the disease free survival (DFS). Cox proportional hazard model was used to identify risk factors for recurrence. Negative tobacco history and stage IA tumors were associated with significantly prolonged DFS after adjusting for co-variates (p=0.001 and p=0.005). Univariate Cox proportional hazards model identified tobacco history and stage 1B as risk factors for recurrence with unadjusted hazard ratio (HR) of 2.8 and 2.0, respectively. After adjusting for covariates, only stage IB was statistically significant predictor of recurrence with a hazard ratio of 2.1 (Confidence Interval (CI) 95% 1.2-3.6; p=0.007). An individualized approach that considers risk factors of stage and smoking history may be useful in determining whether to continue annual CT surveillance after five years post curative therapy for stage I NSCLC.

A Review of Current Concepts In Cancer Chemotherapy

Chemotherapy today is a modality predominantly used to treat metastatic or disseminated malignant neoplastic disease. Depending upon the primary site and stage (extent) of disease, chemotherapy can be geared to be curative or palliative in its intent. Chemotherapy can lead to prolonged disease-free survival in a percentage of patients with certain stages of eieven different malignancies (Table 1). For some of these, chemotherapy can eradicate all malignancy by itself in advanced stages when macroscopic metastatic disease is present. For the three pediatric solid tumors on the list, chemotherapy is used as an adjuvant to surgery and/or irradiation to eradicate microscopic metastatic disease after the local modalities have removed or abiated the primary local and residual disease.

High-dose chemotherapy sensitizes locally advanced esophageal squamous cell carcinoma to PD-1 blockade for a higher pathological complete response rate and survival

BackgroundPD-1 inhibitor and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as the first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). The present study aimed to evaluate the efficacy of PD-1 inhibitors plus different dose intensity neoadjuvant chemotherapy in the treatment of locally advanced ESCC. MethodsPatients with locally advanced but resectable thoracic ESCC, staged as T3 or T4a, N0–3, and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes), were enrolled in this study. The eligible patients received tislelizumab plus different dose intensity chemotherapy for a 21-day cycle with repeated 2–4 cycles before surgery. The primary endpoints are pathological complete response (pCR) and major pathological response (MPR), and the secondary endpoints are objective response rate (ORR), disease control rate (DCR), and disease-free survival (DFS). ResultsFrom November 2019 to February 2022, 122 cases received at least two cycles neoadjuvant chemoimmunotherapy and were evaluated by imaging examination. Subsequently, 99 patients underwent surgery and were evaluated by pathological evaluation. According to chemotherapy dose intensity, the patients were divided into three cohorts: cohort 1 (<80% dose intensity), cohort 2 (80–90% dose intensity), cohort 3 (90–100% dose intensity). All surgery patients underwent minimally invasive esophagectomy (MIE). The average pCR was identified in 22.22%; 16% had pCR in cohort 1, 17.65% had pCR in cohort 2, and 30.00% had pCR in cohort 3. MPR was observed in 9 (36.00%) patients in cohort 1, 18 (52.94%) patients in cohort 2, 22 (55.00%) patients in cohort 3. In univariable and multivariable analysis, dose intensity was significantly associated with MPR (p = 0.048) in patients who underwent esophagectomy. For surviving patients, the median follow-up was 13.76 months after esophagectomy. Compared to cohort 1, cohorts 2 and 3 had better DFS (p = 0.056). In addition, the prognosis of patients with MPR was better than that of patients without MPR (p = 0.014). ConclusionsThe robust antitumor activity of neoadjuvant chemoimmunotherapy for locally advanced but resectable thoracic ESCC was confirmed. More than 80% of chemotherapy dose intensity combined with immunotherapy resulted in a high pCR rate and prolonged DFS.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

Prognostic value of perioperative serum low-density lipoprotein cholesterol level for postoperative prognosis of pancreatic cancer: a retrospective study

BackgroundAs a common malignant tumour, pancreatic cancer (PC) has the worst clinical outcome. Early evaluation of the postoperative prognosis has certain clinical value. Low-density lipoprotein cholesterol (LDL-c), which is mainly composed of cholesteryl esters, phospholipids, and proteins, plays an important role in transporting cholesterol into peripheral tissues. LDL-c has also been reported to be correlated with the occurrence and progression of malignant tumours and can predict postoperative prognosis in various tumours.AimsTo determine correlation between serum LDL-c level and clinical outcome in PC patients after surgery.MethodsData of PC patients that received surgery at our department from January 2015 to December 2021 were retrospectively analysed. Receiver operating characteristic (ROC) curves between perioperative serum LDL-c at different timepoints and survival rate at postoperative 1-year were drawn, and the optimal cut-off value was calculated. Patients were categorized into low and high LDL-c groups, and their clinical data and outcome were compared. Univariate and multivariate analyses were applied to screen out risk markers for poor prognosis of PC patients after surgery.ResultsThe area under the ROC curve of serum LDL-c at 4 weeks after surgery and prognosis was 0.669 (95% CI: 0.581–0.757), and the optimal cut-off value was 1.515 mmol/L. The median disease-free survival (DFS) rates of low and high LDL-c groups were 9 months and 16 months, respectively, and the 1-, 2- and 3-year DFS rates were 42.6%, 21.1% and 11.7% in low LDL-c group, respectively, and, 60.2%, 35.3% and 26.2% in high LDL-c group, respectively (P = 0.005). The median overall survival (OS) rates of low and high LDL-c groups were 12 months and 22 months, respectively, and the 1-, 2- and 3-year OS rates were 46.8%, 22.6% and 15.8% in low LDL-c group, respectively, and 77.9%, 46.8% and 30.4% in high LDL-c group, respectively (P = 0.004). Multivariate analysis confirmed low postoperative 4-week serum LDL-c as independent risk marker for early tumour recrudesce and poor clinical outcome in PC patients.ConclusionHigh postoperative 4-week serum LDL-c is a prognostic marker for prolonged DFS and OS time in PC patients.

Identification and validation of m6A-GPI signatures as a novel prognostic model for colorectal cancer.

In order to develop an N6-methyladenosine-related gene prognostic index (m6A-GPI) that can predict the prognosis in colorectal cancer (CRC), we obtained m6A-related differentially expressed genes (DEGs) based on The Cancer Genome Atlas (TCGA) and m6Avar database, seven genes were screened by weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis. Then, m6A-GPI was constructed based on the risk score. Survival analysis indicated that patients in the lower m6A-GPI group have more prolonged disease-free survival (DFS), and different clinical characteristic groups (tumor site and stage) also showed differential risk scores. In the analysis of the molecular characteristics, the risk score is positively associated with homologous recombination defects (HRD), copy number alterations (CNA), and the mRNA expression-based stemness index (mRNAsi). In addition, m6A-GPI also plays an essential role in tumor immune cell infiltration. The immune cell infiltration in the low m6A-GPI group is significantly higher in CRC. Moreover, we found that CIITA, one of the genes in m6A-GPI was up-regulated in CRC tissues based on real-time RT-PCR and Western blot. m6A-GPI is a promising prognostic biomarker that can be used to distinguish the prognosis of CRC patients in CRC.

Randomized phase II adjuvant trial to compare two treatment durations of icotinib (2 years versus 1 year) for stage II-IIIA EGFR-positive lung adenocarcinoma patients (ICOMPARE study)

Despite the prolonged median disease-free survival (DFS) by adjuvant targeted therapy in non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the relationship between the treatment duration and the survival benefits in patients remains unknown. In this multicenter, randomized, open-label, phase II trial, eligible patients aged 18-75 years with EGFR-mutant, stage II-IIIA lung adenocarcinoma and who had not received adjuvant chemotherapy after complete tumor resection were enrolled from eight centers in China. Patients were randomly assigned (1 : 1) to receive either 1-year or 2-year icotinib (125 mg thrice daily). The primary endpoint was DFS assessed by investigator. The secondary endpoints were overall survival (OS) and safety. This study was registered at ClinicalTrials.gov (NCT01929200). Between September 2013 and October 2018, 109 patients were enrolled (1-year group, n= 55; 2-year group, n= 54). Median DFS was 48.9 months [95% confidence interval (CI) 33.1-70.1 months] in the 2-year group and 32.9 months (95% CI 26.6-44.8 months) in the 1-year group [hazard ratio (HR) 0.51; 95% CI 0.28-0.94; P= 0.0290]. Median OS for patients was 75.8 months [95% CI 64.4 months-not evaluable (NE)] in the 2-year group and NE (95% CI 66.3 months-NE) in the 1-year group (HR 0.34; 95% CI 0.13-0.95; P= 0.0317). Treatment-related adverse events (TRAEs) were observed in 41 of 55 (75%) patients in the 1-year group and in 36 of 54 (67%) patients in the 2-year group. Grade 3-4 TRAEs occurred in 4 of 55 (7%) patients in the 1-year group and in 3 of 54 (6%) patients in the 2-year group. No treatment-related deaths or interstitial lung disease was reported. Two-year adjuvant icotinib was shown to significantly improve DFS and provide an OS benefit in EGFR-mutant, stage II-IIIA lung adenocarcinoma patients compared with 1-year treatment in this exploratory phase II study.

Associations between polymorphisms in leptin and leptin receptor genes and colorectal cancer survival.

Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of LEP and leptin receptor (LEPR) to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collected via questionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) in LEP and LEPR with overall survival (OS), disease-free survival (DFS), and CRC-specific survival. At the gene level, LEP was associated with DFS (P = 0.017), and LEPR was associated with both DFS (P = 0.021) and CRC-specific survival (P = 0.013) in patients with CRC. In single-SNP analysis, LEP rs11763517, LEPR rs9436301, and LEPR rs7602 were associated with DFS after adjustment for multiple testing. The LEPR haplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43-0.93; A-A-G: HR, 0.59; 95% CI, 0.38-0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34-0.86; A-A-G: HR, 0.49; 95% CI, 0.29-0.83). Similar results were observed for DFS. Moreover, significant interactions were found among LEPR rs7602 (A vs. G), LEPR rs1171278 (T vs. C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m2. Polymorphic variations in the LEP and LEPR genes were associated with survival of patients after CRC diagnosis. The LEP/LEPR-CRC survival association was modified by participants' red meat intake and BMI.

Tumor keratin 15 expression links with less extent of invasion and better prognosis in papillary thyroid cancer patients receiving tumor resection.

Keratin 15 (KRT15) is identified as a useful biomarker in several solid tumors, while its clinical role in papillary thyroid cancer (PTC) remains unknown. Herein, this study is intended to explore the correlation of tumor KRT15 with clinical features and survival in PTC patients who received tumor resection. This study retrospectively screened 350 PTC patients who received tumor resection and 50 thyroid benign lesions (TBL) patients. KRT15 in formalin-fixed paraffin-embedded lesion specimens of all subjects was detected by immunohistochemistry (IHC). KRT15 was reduced in PTC patients compared to TBL patients (P < 0.001). Furthermore, KRT15 was negatively associated with tumor size (P = 0.017), extrathyroidal invasion (P = 0.007), pathological tumor (pT) stage (P < 0.001), and postoperative radioiodine application (P = 0.008) in PTC patients. Regarding prognostic value, high KRT15 (cut-off by an IHC value of 3) is linked with prolonged accumulating disease-free survival (DFS) (P = 0.008) and overall survival (OS) (P = 0.008) in PTC patients. Also, the multivariate Cox regression model showed that high KRT15 (vs. low) was an independent factor for longer DFS (hazard ratio = 0.433, P = 0.049), but not for OS (P > 0.050) in PTC patients. Subgroup analyses revealed that KRT15 possessed a better prognostic value in PTC patients with age ≥ 55years, tumor size > 4cm, pathological node stage 1, or pathological tumor-node-metastasis stage ≤ 2 (all P < 0.050). Increased tumor KRT15 associates with a lower invasive degree, prolonged DFS, and OS, revealing its prognostic utility in PTC patients undergoing tumor resection.

Impact of the Number of Harvested Lymph Nodes on Long-Term Survival in Node-Negative Non–Small-Cell Lung Cancer: Based on Clinical Stage But Not Pathological Stage

BackgroundWe aimed to investigate the impact of the number of harvested lymph nodes (LNs) on the overall survival (OS) and disease-free survival (DFS) of patients with clinical node-negative (cN0) non–small-cell lung cancer (NSCLC). Patients and MethodsA total of 2247 patients with cN0 NSCLC between 2001 and 2014 were included. Scatter plots of hazard ratios from Cox proportional hazards models against the number of harvested LNs were created, and curves were fitted using a LOWESS smoother. Chow test was used to determine the cut-off points for the optimal number of harvested LNs. Long-term survival was compared between groups divided by the cut-off points. ResultsThe increasing numbers of harvested LNs and N2 level LNs were independent factors favoring OS and DFS. Seventeen LNs and 10 N2 level LNs were determined as the optimal cut-off points. The patients with ≥17 harvested LNs had a better OS (P = .001) and DFS (P = .002), while the patients with ≥10 harvested N2 level LNs also had a better OS (P < .001) and DFS (P = .001). The increasing numbers of harvested LNs and N2 level LNs were independent prognostic factors associated with prolonged OS and DFS only in patients with clinical T2 (cT2) NSCLC. ConclusionsThe increasing numbers of harvested LNs and N2 level LNs were associated with better OS and DFS in cN0 NSCLC patients that were suitable for lobectomies. At least 17 LNs and 10 N2 level LNs were required to be harvested, especially in cT2 patients.

Current trends in perioperative treatment of resectable gastric cancer.

In the last few decades, the treatment strategy for locally advanced resectable gastric cancer (GC) has shifted to a multimodal approach, which potentially decreases recurrence risk and improves survival rates. Perioperative therapy leads to downstaging, increased curative resection rates, and prolonged disease-free and overall survival, by preventing micrometastases in patients with resectable GC. Application of neoadjuvant therapy provides information about tumor biology and in vivo sensitivity. A consensus regarding the therapeutic approach for non-metastatic GC does not exist, and many clinical trials aim to clarify this aspect. Advances in precision medicine and the role of immunotherapy have been the focus of research in GC treatment. Herein, the current status and possible future developments of perioperative therapy for locally advanced resectable GC are reviewed, based on the most recent randomized clinical trials.

Longer interval between neoadjuvant chemoradiotherapy and surgery is associated with improved pathological response, but does not accurately estimate survival in patients with resectable esophageal cancer.

Neoadjuvant chemoradiotherapy (nCRT) has been shown to reduce tumor burden and achieve tumor regression in patients with esophageal cancer (ESC). However, the most beneficial time interval between the administration of nCRT and surgery remains unclear. Therefore, the aim of the present study was to explore the association of the duration of time between nCRT and surgery with the prognosis of patients with ESC. Patients with ESC who received nCRT following surgical resection (n=161) were reviewed and divided into the prolonged time interval group (time interval ≥66 days) and the short time interval group (time interval <66 days), according to the median value. Subsequent analysis revealed that the prolonged time interval group achieved a higher pathological complete response (pCR) rate compared with the short time interval group (49.4 vs. 26.3%; P=0.003). Furthermore, multivariate logistic regression analysis showed that it was possible to independently estimate a higher pCR rate based on a prolonged time interval (odds ratio, 2.131; P=0.042). However, no association between a prolonged time interval and disease-free survival (DFS) was detected using Kaplan-Meier curves (P=0.252) or multivariate Cox regression (P=0.607) analyses. Similarly, no association was identified between a prolonged time interval and overall survival (OS; P=0.946) based on Kaplan-Meier curve analysis, and subsequent multivariate Cox regression analyses showed that the time interval also failed to independently estimate OS (P=0.581). Moreover, female sex (P=0.001) and a radiation dose ≥40 Gy (P=0.039) served as independent factors associated with a higher pCR rate, and the pCR rate was an independent predictor of favorable DFS (P=0.002) and OS (P=0.015) rates. In conclusion, the present study revealed that a prolonged time interval from nCRT to surgery was associated with a higher pCR rate, but it failed to estimate the survival profile of patients with ESC.

Automated assessment of necrosis tumor ratio in colorectal cancer using an artificial intelligence‐based digital pathology analysis

AbstractBackgroundWith the advance in digital pathology and artificial intelligence (AI)‐powered approaches, necrosis is proposed as a marker of poor prognosis in colorectal cancer (CRC). However, most previous studies quantified necrosis merely as a tissue type and patch‐level segmentation. Thus, it was worth exploring and validating the prognostic and predictive value of necrosis proportion with a pixel‐level segmentation in large multicenter cohorts.MethodsA semantic segmentation model was trained with 12 tissue types labeled by pathologists. Segmentation was performed using the U‐net model with a subsequently derived necrosis tumor ratio (NTR). We proposed the NTR score (NTR‐low or NTR‐high) to evaluate the prognostic and predictive value of necrosis for disease‐free survival (DFS) and overall survival (OS) in the development (N = 443) and validation cohorts (N = 333) using 75% as a threshold.ResultsThe 2‐category NTR was an independent prognostic factor and NTR‐low was associated with significant prolonged DFS (unadjusted HR for high vs. low 1.72 [95% CI 1.19–2.49] and 1.98 [1.22–3.23] in the development and validation cohorts). Similar trends were observed for OS. The prognostic value of NTR was maintained in the multivariate analysis for both cohorts. Furthermore, a stratified analysis showed that NTR‐high was a high risk with adjuvant chemotherapy for OS in stage II CRC (p = 0.047).ConclusionAI‐based pixel‐level quantified NTR has a stable prognostic value in CRC associated with unfavorable survival. Additionally, adjuvant chemotherapy provided survival benefits for patients with a high NTR score in stage II CRC.