Predictor Of Prolonged Progression-free Survival Research Articles

Circulating tumor cells help differentiate benign ovarian lesions from cancer before surgery: A literature review and proof of concept study using flow cytometry with fluorescence imaging.

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Transarterial chemoembolization with insertion of radioactive seeds for hepatocellular carcinoma.

For patients diagnosed with hepatocellular carcinoma (HCC) not eligible for surgical tumor resection, transarterial chemoembolization (TACE) is commonly employed as a therapeutic strategy. After TACE is complete, a variety of other therapeutic approaches can be employed to improve patient overall survival (OS) and progression-free survival (PFS). This study was developed with the goal of comparing the relative clinical efficacy and long-term outcomes observed in HCC patients who underwent combination TACE and radioactive seed insertion (RSI) treatment to those of patients who only underwent TACE treatment. This retrospective analysis included a total of 80 patients with HCC who underwent treatment via TACE with (n = 39) or without (n = 41) RSI. Treatment responses and long-term outcomes in these two groups were compared with one another. The baseline characteristics of both groups were comparable. None of the patients experienced adverse complications related to treatment. Individuals in the combination treatment group experienced complete response (59.0% vs. 22.0%, p = 0.001) and total response (92.3% vs. 58.5%, p = 0.001) rates that were significantly better than those of patients that underwent TACE alone. Combination treatment was also associated with significant prolongation of patient PFS (13 vs. 7 months, p = 0.019) and OS (23 vs. 15 months, p = 0.005), with Cox regression analyses identifying combination treatment as a predictor of prolonged PFS and OS. These data suggest that a combination of TACE and RSI can contribute to significant improvements in HCC patient therapeutic response rates, OS, and PFS relative to TACE alone.

Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small-cell lung cancer

BackgroundMost patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this...

Effects of Neoadjuvant Chemotherapy in Ovarian Cancer Patients With Different Germline BRCA1/2 Mutational Status: A Retrospective Cohort Study.

BackgroundWhether neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) against primary debulking surgery (PDS) has a differential effect on prognosis due to Breast Cancer Susceptibility Genes (BRCA)1/2 mutations has not been confirmed by current studies.MethodsAll patients included in this retrospective study were admitted to Qilu Hospital of Shandong University between January 2009 and June 2020, and germline BRCA1/2 mutation were tested. Patients in stage IIIB, IIIC, and IV, re-staged by International Federation of Gynecology and Obstetrics (FIGO) 2014, were selected for analysis. All patients with NAC received 1-5 cycles of platinum-containing (carboplatin, cisplatin, or nedaplatin) chemotherapy. Patients who received maintenance therapy after chemotherapy were not eligible for this study. All relevant medical records were collected.ResultsA total of 322 patients were enrolled, including 112 patients with BRCA1/2 mutations (BRCAmut), and 210 patients with BRCA1/2 wild-type (BRCAwt). In the two groups, 40 BRCAmut patients (35.7%) and 69 BRCAwt patients (32.9%) received NAC. The progression-free survival (PFS) of BRCAmut patients was significantly reduced after NAC (median: 14.9 vs. 18.5 months; p=0.023); however, there was no difference in overall survival (OS) (median: 75.1 vs. 72.8 months; p=0.798). Whether BRCAwt patients received NAC had no significant effect on PFS (median: 13.5 vs. 16.0 months; p=0.780) or OS (median: 54.0 vs. 56.4 months; p=0.323). Multivariate analyses in BRCAmut patients showed that the predictors of prolonged PFS were PDS (p=0.001), the absence of residual lesions (p=0.012), and FIGO III stage (p=0.020); Besides, PARP inhibitor was the independent predictor for prolonged OS in BRCAmut patients (p=0.000), for BRCAwt patients, the absence of residual lesions (p=0.041) and history of PARP inhibitors (p=0.000) were beneficial factors for OS prolongation.ConclusionsFor ovarian cancer patients with FIGO IIIB, IIIC, and IV, NAC-IDS did not adversely affect survival outcomes due to different BRCA1/2 germline mutational status.

High Mast Cell Density Predicts a Favorable Prognosis in Patients with Pancreatic Neuroendocrine Neoplasms

Introduction: Mast cells are involved in allergic diseases, immune regulation, and tumor microenvironment modulation, with both pro- and anti-tumorigenic functions, and could serve as a prognostic factor in various cancers. However, their potential role in pancreatic neuroendocrine neoplasms (PanNENs) is largely unknown. Here, our aim was to investigate the presence of mast cells in PanNENs and evaluate their association with clinicopathological parameters and other common tumor-infiltrating immune cells. Methods: Tissue microarrays containing PanNEN samples from 187 patients were constructed and stained immunohistochemically for CD117, CD15, CD68, CD3, CD4, and CD8. Immune cells were counted from four high-power fields (HPFs; ×400) at maximal concentrations, and the mean counts were calculated per HPF. The cutoff values were set by X-tile. Results: The median (interquartile range) counts of CD117⁺ mast cells, CD15⁺ neutrophils, CD68⁺ macrophages, CD3⁺ T cells, and CD4⁺ T cells were 3.5 (2.0–6.0), 3.0 (1.3–6), 3.8 (2.5–5.8), 13 (8.0–24.0), and 2.0 (1.0–4.0)/HPF, respectively. CD8⁺ T cells were not detected. The cutoff values for these immune cells were 1.5/HPF, 6/HPF, 4.8/HPF, 32.5/HPF, and 2/HPF, respectively. Low mast cell density was correlated with higher grades, noninsulinoma, and advanced stages. Moreover, high mast cell infiltration was associated with elevated CD4⁺ T cell and CD15⁺ neutrophil counts. Multivariate analysis revealed that high mast cell density was an independent predictor of prolonged progression-free survival in the entire cohort; in pancreatic neuroendocrine tumors; and in intermediate-grade, noninsulinoma, and advanced stage subgroups. Conclusions: These findings suggest a protective role of mast cells in PanNENs.

EGFR Gene Polymorphism Predicts Improved Outcome in Patients With EGFR Mutation-positive Non–small cell Lung Cancer Treated With Erlotinib

BackgroundPatients with advanced-stage non–small cell lung cancer with epidermal growth factor receptor (EGFR) mutations are successfully treated with tyrosine kinase inhibitors (TKIs). However, treatment outcome varies significantly. Previously, we found the polymorphism 181946C>T (rs2293347) located in exon 25 of the EGFR gene to be a predictor of improved outcome. However, these data were based on a subgroup analysis. Furthermore, other minor studies have found conflicting data. Thus, the aim of this study was to demonstrate the association of 181946C>T with clinical outcome in an independent cohort of EGFR-mutated patients treated with erlotinib. Patients and MethodsSeventy-five patients were prospectively enrolled. Blood samples were collected, and genotype for 181946C>T was determined by allele-specific polymerase chain reaction. Genotype was correlated with outcome. ResultsIn 73 patients, 181946C>T was successfully measured. Patients harboring the 181946CT genotype had a significantly longer median progression-free survival compared with patients harboring the 181946CC genotype (49.9 months [95% confidence interval (CI), 5.9-93.9 months] versus 11.1 months (95% CI, 7.4-14.9 months); P = .020). Moreover, a significantly longer median overall survival of 65.6 months (95% CI, 11.0-120.3 months) versus 31.2 months (95% CI, 10.9-51.6 months) was found (P = .019). Both results remained significant in a multivariate analysis adjusting for potential confounders. ConclusionWe demonstrate that the 181946C>T polymorphism is a significant predictor of prolonged progression-free survival and overall survival in an independent cohort of EGFR mutation-positive patients treated with erlotinib. The polymorphism could be an important predictor of treatment response in these patients. A large multicenter cohort study involving other concurrent genetic alterations is warranted.

Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma.

453 Background: Increases in mean corpuscular volume (MCV) and hypothyroidism have been observed in patients on sunitinib treatment. We characterized tyrosine kinase-associated macrocytosis in metastatic renal cell carcinoma (mRCC) patients and its relationship, along with thyroid dysfunction, to progression-free survival (PFS). Methods: A retrospective chart review was performed on patients treated with sunitinib and/or sorafenib (01/2005-01/2011). Data pertaining to the development of macrocytosis was analyzed in association with our previous data on thyroid dysfunction in these patients. We assessed PFS, as clinically defined by the treating provider. Results: Seventy-four patients with 103 treatment periods for sorafenib (47) and sunitinib (56) were analyzed. Macrocytosis was found in 55% and 8% of sunitinib and sorafenib treatment periods, respectively (p&lt;0.001). Focusing on the sunitinib-treated patients for all further analysis, the median PFS was 11 months (mo) (95% CI, 6-19). Median PFS was 21 mo (95% CI, 11-25) for patients who developed macrocytosis compared to 4 mo (95% CI, 3-8) in normocytic patients (p=0.0001). The time to development of macrocytosis did not affect the degree of macrocytosis observed (p=0.47). Macrocytosis and hypothyroidism were both significant predictors of prolonged PFS in our cohort. The greatest difference in PFS was noted between patients who developed both macrocytosis and hypothyroidism (25 mo) versus those who remained both normocytic and euthyroid (5 mo) (p&lt;0.0001). Conclusions: Sunitinib-related macrocytosis is associated with a prolonged PFS in mRCC. The concurrent development of both hypothyroidism and macrocytosis in this setting was associated longer PFS compared to either alone. Increased MCV may be used as a biomarker for sunitinib response in this setting. [Table: see text]

Genotype Correlations With Blood Pressure and Efficacy From a Randomized Phase III Trial of Second-Line Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma

BackgroundIn the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported. Patients and MethodsDNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1α with outcomes for blood pressure (BP; Grade ≥ 3 hypertension, diastolic BP > 90 mm Hg, and increase ≥ 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS. ResultsGenotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%. ConclusionNo SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment.

Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.

Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers. This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured. Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P<0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P<0.0001, P=0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis. This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.

Circadian robustness as an independent predictor of prolonged progression-free survival (PFS) and overall survival (OS) in 436 patients with metastatic colorectal cancer (mCRC).

464 Background: The rest-activity rhythm is a biomarker of the circadian timing system (CTS), whose disruption accelerates cancer progression in experimental models. Prior studies in cancer pts identified a reliable measure of CTS function in cancer pts based on non invasive wrist actigraphy monitoring. Methods: The prognostic value of I&lt;O, the ratio between activity counts in-bed vs out-of-bed, was explored for PFS and OS in mCRC. The rest-activity rhythm was recorded for &gt;48 h in 436 mCRC pts from 3 international cohorts. Data were stratified per cohort, and analyzed with Kruskall-Wallis ANOVA, log rank tests, and multivariate Cox analyses. Results: Median age was 59.2 y. Pts were mainly men (62.6%); had good performance status (PS = 0, 58.2%; 1, 33%); &gt; 2 metastatic sites (51.6%); metastases in liver (79%) or lung (38.8%); were chemotherapy-naïve (54.6%). After baseline actigraphy recording, pts received a median of 8 courses of oxaliplatin- or irinotecan-based chemotherapy, including chronomodulated schedules (chrono; 81.4%). Despite a strong correlation with PS (p&lt; 0.0001), I&lt;O independently influenced both PFS and OS. Thus, both median PFS and OS nearly doubled in the pts with I&lt;O above 97.5% (upper two quartiles) as compared to those with I&lt;O below 93.2% (lowest quartile). Median PFS ranged from 4.8 to 10.6 months (log rank, p&lt;0.001) and median OS from 10.1 to 20.6 months (p&lt;0.001). In multivariate analyses, I&lt;O ranked as the second best independent predictor of PFS, after metastases surgery, with a hazard ratio (HR) of 0.967 [95% C.L., 0.95-0.98] (p&lt;0.001). I&lt;O ranked as first independent predictor of OS, with a HR of 0.95 [0.94-0.97] (p&lt;0.001). Forrest plots revealed consistent HR of I&lt;O for PFS and OS in each cohort. Conclusions: The circadian biomarker indicator I&lt;O is a robust, consistent and independent quantitative predictor of both PFS and OS in mCRC pts. Rest-activity rhythm monitoring deserves further testing for helping accurate determination of mCRC prognosis. The biological significance of I&lt;O implies that specific treatments of circadian disruption could enhance survival in cancer pts.

High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients.

To examine the prognostic factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in 100 consecutively treated women undergoing autologous stem-cell transplant for advanced ovarian cancer. From October 1989 to February 1996, we transplanted 100 patients with ovarian cancer following chemotherapy with high-dose carboplatin, mitoxantrone, and cyclophosphamide with or without cyclosporine (n = 70); melphalan and mitoxantrone with or without paclitaxel (n = 25); or other regimens (n = 5). Their median age was 48 years (range, 23 to 65), 70% had papillary serous histology, 72% had grade III tumors, 66% were platinum-resistant, and 61% had > or = 1 cm bulk. The median number of prior regimens was two (range, one to six). Univariate and multivariate analyses were performed to examine age (< v > or = mean), stage, initial bulk, histology, grade, response to initial therapy, number of prior regimens, time from diagnosis to transplant, transplant regimen, platinum sensitivity, and bulk (< v > or = 1 cm) at transplant. The median PFS and OS times for the 100 patients were 7 and 13 months. A stepwise Cox proportional hazards model identified tumor bulk (P = .0001), and cisplatin sensitivity (P = .0249) as the best predictors of PFS. Age (P = .0017), bulk at transplant (P = .0175), and platinum sensitivity (P = .0330) provided the best prediction of OS. The median PFS and OS times for the 20 patients with platinum-sensitive, < or = 1-cm disease were 19 and 30 months. No differences in OS were seen when chemotherapy or surgery was used to achieve a minimal disease state. Before consideration of high-dose therapy for recurrent/persistent advanced ovarian cancer, patients should undergo debulking surgery or chemotherapy to achieve a minimal disease state. Patients with platinum-resistant, bulky disease should not be transplanted. The optimal patients for this therapy may be those with minimal disease responsive to initial chemotherapy.