Age alone is not a predictor for survival in glioblastoma

Over half of glioblastoma (GBM) cases are diagnosed in patients older than 65 years. Their median overall survival (OS) is 4–5 months, compared with 12–14 months in patients younger than 70 years. This retrospective audit aims to identify patterns of care and survival of patients diagnosed with GBM at a single institution in Melbourne, Australia. Consecutive histological diagnoses of adult primary GBM from January 2010 to December 2012 were retrospectively identified from medical records. Demographic, treatment and survival characteristics were recorded until death, with follow-up to January 1st 2015. Survival was estimated by Kaplan–Meier method. Planned, sub-group analyses were conducted using multivariate Cox proportional hazards model to identify differences between elderly and younger cohorts, as well as ECOG. 165 patients were identified (36?% aged ≥70 years). Those ≥70 years had a poorer performance status (ECOG 3–4: 27 vs 10?%, p?=?.005); poorer median OS (2.6 vs 11.5 months, p?<?.001); and were less likely to receive adjuvant treatment (no treatment: 40 vs 16?%, p?<?.001) compared with patients <70 years. Age was not a significant predictor of poorer os (HR 1.0; 0.99–1.03; p?>?.05), after adjusting for other clinical factors. Significant predictors of poorer os were poor performance status (p?=?.001), bilateral tumours (p?=?.04), biopsy only (p?=?.001), and no adjuvant treatment (p?<?.001). In patients diagnosed with GBM, those older than 70 years often present with poor performance status, are less likely to receive adjuvant treatment and have inferior os compared with younger patients. Treatment recommendations should be based on performance status/fitness, not age alone.     

One decade of glioblastoma multiforme surgery in 342 elderly patients: what have we learned?

To assess the utilization and outcomes of adjuvant monotherapy with hypofractionated radiation (RT) among elderly patients not receiving traditional adjuvant chemoradiotherapy (cRT) for glioblastoma multiforme (GBM). A retrospective analysis using the National Cancer Data Base with GBM patients aged 65 years or older treated between 2005 and 2012 was conducted. Patients who underwent hypofractionated RT (40 Gy), conventional RT (60 Gy), chemotherapy, or best supportive care alone were included. Statistical methods included logistic regression for utilization and Cox regression for survival analysis. A total of 9556 patients were analyzed. On multivariate analysis (compared to those receiving conventional RT), patients more likely to be treated with hypofractionated RT were older (75–84 years old OR 2.05; p?<?0.01 and ≥?85 years old OR 3.32; p?<?0.01), with a Charlson/Deyo score of 2 or higher (OR 1.80; p?=?0.05), from communities?>?50 miles from their treatment facility (50–100 miles OR 8.03; p?<?0.01 and >?100 miles OR 7.16; p?<?0.01), treated at an Academic/Research facility (OR 2.85; p?=?0.04), and diagnosed between 2011 and 2012 (OR 4.15; p?<?0.01). On Cox regression, hypofractionated RT (HR 0.65; p?<?0.01), conventional RT (HR 0.60; p?<?0.01), and chemotherapy alone (HR 0.69; p?<?0.01) were all associated with decreased risk of death compared to no adjuvant therapy. Among patients receiving adjuvant treatment, utilization of hypofractionated RT increased from 7 to 19% during the study period. Among elderly patients with GBM not receiving cRT, the utilization of adjuvant monotherapy with hypofractionated RT has increased over time. Retrospective evidence suggests it may be better than best supportive care alone and as good as conventionally fractionated RT alone.     

Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide

Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P?P?P?P?P?=?.009) and overall survival (HR 1.52, 95?% CI 1.04–2.21; P?=?.029). CSF OPN is a potential biomarker in CNSL.     

Survival benefit of hepatic resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis

Background

No consensus treatment has been reached for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Hepatic resection (HR) and transarterial chemoembolization (TACE) have been recommended as effective options, but which is better remains unclear. This meta-analysis is to compare the effectiveness of HR and TACE for HCC with PVTT patients.

Methods

The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched for comparing HR and TACE treating PVTT.

Results

Twelve retrospective studies with 3129 patients were included. A meta-analysis of 11 studies suggested that the 1-, 2-, 3-, and 5-year overall survival (OS) rates (OR?=?0.48, 95% CI?=?0.41–0.57, I² =?37%, P?<?0.00001; OR?=?0.21, 95% CI?=?0.12–0.38, I² =?43%, P?<?0.00001; OR?=?0.35, 95% CI?=?0.28–0.44, I² =?53%, P?<?0.00001; OR?=?0.28, 95% CI?=?0.14–0.54, I² =?72%, P?=?0.0001, respectively) favored HR over TACE. In a subgroup analysis, HR had better 1-, 2-,3, 5-year OS for type I PVTT (OR?=?0.33, 95% CI?=?0.17–0.64, I² =?20%, P?=?0.001; OR?=?0.32, 95% CI?=?0.16–0.63, I2?=?0%, P?=?0.001; OR?=?0.18, 95% CI?=?0.09–0.36, I2?=?0%, P?<?0.00001; OR?=?0.07, 95% CI?=?0.01–0.32, I2?=?0%, P?=?0.0006, respectively) and better 1-, 3-, and 5-year OS for type II PVTT (OR?=?0.37, 95% CI?=?0.20–0.70, I² =?59%, P?=?0.002; OR?=?0.22, 95% CI?=?0.13–0.39, I² =?0%, P?<?0.00001; OR?=?0.16; 95% CI?=?0.03–0.91; I² =?51%, P?=?0.04, respectively). There was no difference in 1-, 3-, or 5-year OS between HR and TACE for type III PVTT (OR?=?0.86, 95% CI?=?0.61–1.21, I² =?0%, P?=?0.39; OR?=?0.83, 95% CI?=?0.42–1.64, I² =?0%, P?=?0.59; OR?=?0.59, 95% CI?=?0.06–-6.04, I² =?65%, P?=?0.66, respectively).

Conclusions

HR may lead to longer OS for some selected HCC patients with PVTT than TACE, especially for type I or II PVTT, with less difference being observed for type III or IV PVTT.

     

The effect of post-progression survival on overall survival among patients with sensitive relapse of small cell lung cancer

Recent studies have suggested that, among patients with advanced lung cancer, subsequent treatment after failure of first-line or second-line chemotherapy has a greater effect on overall survival (OS) than tumor shrinkage or progression-free survival (PFS). However, no studies have examined this issue among patients with sensitive relapse of small cell lung cancer (SCLC). We retrospectively evaluate 77 patients with sensitive relapse of SCLC who received second-line chemotherapy after first-line platinum doublet chemotherapy between January 1999 and November 2013. The analyses included patient characteristics, treatment parameters, tumor shrinkage, PFS, post-progression survival (PPS), and OS. Spearman rank correlation analysis and linear regression analysis revealed that PPS was strongly correlated with OS (r?=?0.91, p?<?0.01, R²?=?0.96), PFS was moderately correlated with OS (r?=?0.58, p?<?0.01, R²?=?0.28), and tumor shrinkage was weakly correlated with OS (r?=?0.34, p?<?0.01, R²?=?0.12). A multivariate Cox proportional hazards model with a stepwise regression procedure revealed that PPS was significantly associated with age at the start of second-line chemotherapy, best response to second-line and third-line chemotherapy, and the number of regimens after progression beyond second-line chemotherapy (p?<?0.05). These findings suggest that PPS has a stronger effect than PFS on OS among patients with sensitive relapse of SCLC. Thus, response to second-line chemotherapy and subsequent treatment for disease progression after second-line chemotherapy may be important factors that influence OS.     

The effect of dose escalation for large squamous cell carcinomas of the anal canal

Purpose

Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (>?5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size.

Methods/patients

The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors?>?5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan–Meier, and Cox proportional hazards for overall survival (OS).

Results

In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p?=?0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR?=?0.998, CI 0.805–1.239, p?=?0.9887). On multivariate analysis, high-dose RT (HR?=?0.948, CI 0.757–1.187, p?=?0.6420) was not associated with improved OS but older age (HR?=?1.535, CI 1.233–1.911, p?=?0.0001), male sex (HR?=?1.695, CI 1.382–2.080, p?<?0.0001), comorbidities (HR?=?1.389, CI 1.097–1.759, p?=?0.0064), and long RT (HR?=?1.299, CI 1.047–1.611, p?=?0.0173) were significantly associated with decreased OS.

Conclusions

There was no observed difference in OS for dose escalation of anal cancers?>?5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

     

Low Baseline Serum Sodium Concentration Is Associated with Poor Clinical Outcomes in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy

Background

A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO).

Objective

Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO.

Patients and Methods

We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model.

Results

Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15–0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80–4.80; P?<?.001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70–3.90; P?<?.001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS.

Conclusions

Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation.

     

Is upfront stereotactic radiosurgery a rational treatment option for very elderly patients with brain metastases? A retrospective analysis of 106 consecutive patients age 80 years and older

Background

Advanced age has been shown to be a factor predicting poor survival in patients with brain metastases (BM). There have been only a few studies focusing on stereotactic radiosurgery (SRS) for elderly BM patients. The present study aimed to investigate the efficacy and limitations of SRS for very elderly BM patients.

Methods

This was a retrospective observational study analyzing 106 consecutive patients (69 males/37 females) age 80 years and older who received upfront Gamma Knife SRS for BM between January 2009 and October 2015. The median age was 84 years, and the median Karnofsky performance status (KPS) was 70. Fifty-two patients had a solitary BM, and others multiple BM. The median cumulative tumor volume was 3.9 mL and the median dose prescribed was 20 Gy. Overall survival (OS), neurological death rates and distant and local intracranial tumor control rates were analyzed.

Results

No patients were lost to follow-up. Six-month and 12-month OS rates were 54% and 32%, respectively. The median OS time was 7.1 months. Competing risks analysis showed that 6-month and 12-month neurological death rates were 8% and 11%, respectively. In total, 245 / 311 tumors (79%) in 82 patients (77%) with sufficient radiological follow-up data were evaluated. Six-month and 12-month distant BM recurrence rates (per patient) after SRS were 17% and 25%, respectively. Six-month and 12-month rates of local tumor control (per lesion) were 94% and 89%, respectively. Repeat SRS, salvage WBRT and surgical resection were subsequently required in 25, 4 and 1 patient, respectively. Proportional hazard regression analysis showed that KPS?≥?70 (HR: 0.444, P?<?.001), controlled primary disease/no extracranial metastases (HR: 0.361, P?<?.001) and female sex (HR: 0.569, P?=?0.028) were independent factors predicting better OS. Similarly, tumor volume (>2 mL) was the only factor predicting a higher rate of local control failure (HR: 12.8, P?=?0.003).

Conclusions

The present study suggested an upfront SRS strategy to offer a feasible and effective treatment option for very elderly patients with limited BM. In the majority of patients, neurological death could be delayed or even prevented.

     

Preoperative chemoradiation therapy induces primary-tumor complete response more frequently than chemotherapy alone in gastric cancer: analyses of the National Cancer Database 2006–2014 using propensity score matching

Background

The benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone (“chemotherapy” hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer.

Methods

Patients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS.

Results

We identified 8464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p?<?0.001). After propensity score matching, a total of 2408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76–2.95; p?<?0.0001) and higher frequency of R0 resection (92 vs. 86%; p?<?0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92–1.15; p?=?0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups.

Conclusions

In this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.

     

Serum amyloid A1 is upregulated in human glioblastoma

Serum amyloid A1 (SAA1) is a sensitive acute phase reactant primarily produced by the liver in response to acute inflammation. We have recently shown that SAA affects proliferation, migration, and invasion of glioblastoma cell lines, which suggest its participation in the malignant process. Consistently, levels of SAA have been used as a non-invasive biomarker for the prognosis of many cancers. In this study, we aimed to investigate SAA serum levels and expression of SAA genes in human astrocytomas tissues. Serum and tissue samples were obtained from patients with astrocytoma grades I to III and glioblastoma (GBM or grade IV). Levels of circulating SAA were significantly higher in the serum of patients with AGII-IV when compared to non-neoplastic samples derived from non-neoplastic patients (NN) (p?>?0.0001). Quantitative real time PCR (qRT-PCR) of 148 astrocytomas samples (grades I-IV) showed that SAA1 mRNA was significantly higher in GBM when compared to AGI-III and NN samples (p?<?0.0001). Immunohistochemistry analysis revealed cytoplasmic positivity for SAA in GBM. There was no correlation of SAA1 with clinical end-point of overall survival among GBM patients. However, it was found a positive correlation between SAA1 and genes involved in tumor progression, such as: HIF1A (r?=?0.50; p?<?0.00001), CD163 (r?=?0.52; p?<?0.00001), CXCR4 (r?=?0.42; p?<?0.00001) and CXCR7 (r?=?0.33; p?=?0.002). In conclusions, we show that astrocytoma patients have increased levels of serum SAA and SAA1 is expressed and secreted in GBM, and its co-expression with tumor-related genes supports its involvement in GBM angiogenesis and progression.     

Radiotherapy plus temozolomide in elderly patients with glioblastoma: a “real-life” report

Background

The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a “real-life” patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/? temozolomide regimens.

Methods

From 2003 to 2016, 104 patients ≥?70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria.

Results

Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70–88), and the median Karnofsky performance status (KPS) was 70 (30–100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT?+?TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT?+?TMZ (P?=?0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P?=?0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26–0.86], P?=?0.014), ii) RPA class (HR: 2.15 [1.17–3.95], P?=?0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33–0.88], P?<?0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor.

Conclusions

These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

     

RETRACTED ARTICLE: The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials

Objective

To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis.

Method

Randomized trials of EGFR-TKIs as treatment for advanced NSCLC were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs in the selected patients by EGFR-mutation status were calculated.

Results

Out of 2134 retrieved articles, 30 randomized controlled trials (RCTs) enrolling more than 4053 patients with wild-type EGFR tumors and 1592 patients with mutant EGFR tumors were identified. For EGFR mutant patients, EGFR-TKIs treatment improved progression-free survival (PFS) compared with chemotherapy: the summary HRs were 0.41 (p?<?0.00001) for the first-line setting and 0.46 (p?=?0.02) for second/third-line setting, respectively. Also, the same superior trend was found with TKIs maintenance over placebo (HR?=?0.14, p?<?0.00001) and with TKIs combined with chemotherapy over chemotherapy (HR?=?0.49, p?=?.002) in both the first-line and maintenance therapy settings. For EGFR wild-type patients, EGFR-TKIs have fared worse than chemotherapy in the first-line setting (HR?=?1.65, p?=?.03) and in the second/third-line setting (HR?=?1.27, p?=?.005). However, EGFR-TKIs maintenance still produced a reduction of 19 % in the risk of progression over placebo (HR?=?0.81, p?=?.02). Furthermore, EGFR-TKIs added to chemotherapy as first-line treatment resulted in an improvement of PFS over chemotherapy alone in such wild-type EGFR patients (HR?=?0.82, p?=?.03). In overall survival (OS) analysis, only EGFR-TKIs single agent was inferior to chemotherapy in EGFR wild-type patients (HR?=?1.13, p?=?.02). No statistically significant difference in terms of OS was observed in any other subgroup analysis.

Conclusions

For EGFR mutant patients, EGFR-TKIs therapy produced a prominent PFS benefit in all settings. Among EGFR wild-type patients, EGFR-TKIs were inferior to chemotherapy both for first-line treatment and for second/third-line treatment. However, EGFR-TKIs maintenance and addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such EGFR wild-type patients.

     

Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy

Purpose

Capecitabine has been studied as a radiosensitizer, and our study seeks to examine the association of concurrent capecitabine/radiation therapy (RT) on event-free- (EFS) and overall survival (OS) in women with breast cancer (BC) with residual disease after neoadjuvant chemotherapy (NAC).

Methods/patients

In a retrospective study of women with BC who received adriamycin/taxane-based NAC from 2004–2016, we identified 21 women administered concurrent capecitabine/RT. To assess differences in survival, we selected a clinical control cohort (n?=?57) based on criteria used to select patients for capecitabine/RT. We also created a matched cohort (2:1), matching on tumor subtype, pathological stage and age (<?50 or 50+ years). Differences in EFS, using STEEP criteria, and OS, using all-cause mortality, between those who received capecitabine/RT and controls were assessed.

Results

Of the 21 women who received capecitabine/RT, median age was 52 years. The majority were pathologic stage III (n?=?15) and hormone receptor-positive/HER2-negative BC (n?=?20). In those receiving capecitabine/RT, there were 9 events, compared with 14 events in clinical and 10 events in matched controls. Capecitabine/RT was associated with worse OS in clinical (HR 3.83 95% CI 1.12–13.11, p?=?0.03) and matched controls (HR 3.71 95% CI 1.04–13.18, p?=?0.04), after adjusting for clinical size, pathological stage and lymphovascular invasion. Capecitabine/RT was also associated with a trend towards worse EFS in clinical (HR 2.41 95% CI 0.86–6.74, p?=?0.09) and matched controls (HR 2.68 95% CI 0.91–7.90, p?=?0.07) after adjustment.

Conclusion

Concurrent capecitabine/RT after NAC is associated with worse survival and should be carefully considered in BC.

     

Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma

The aim of this study was to determine the clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in glioblastoma (GBM). In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in >?5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase-1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan–Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P?=?0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P?=?0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P?=?0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P?<?0.001 and P?=?0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P?<?0.001), and IDH-1 wild type status (P?=?0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis.     

Impact of smoking history on the outcomes of women with early-stage breast cancer: a secondary analysis of a randomized study

To assess the impact of smoking history on the outcomes of early-stage breast cancer patients treated with sequential anthracyclines–taxanes in a randomized study. This is a secondary analysis of patient-level data of 1242 breast cancer patients referred for adjuvant chemotherapy in the BCIRG005 clinical trial. Overall survival was assessed according to smoking history through Kaplan–Meier analysis. Univariate and multivariate Cox regression analyses of factors affecting overall and relapse-free survival were subsequently conducted. Factors that were evaluated included: age, performance status, number of chemotherapy cycles, T stage, lymph node ratio, estrogen receptor status, adjuvant radiotherapy and smoking history. Kaplan–Meier analysis of overall survival according to smoking status (ever smoker vs. never smoker) was conducted. There was a trend toward a better overall survival among never smokers compared to ever smokers; however, it was not statistically significant (P?=?0.098). The following factors were associated with better overall survival in multivariate analysis: older age (P?=?0.011), complete chemotherapy course (P?=?0.002), lower T stage (P?<?0.0001), lower lymph node ratio (P?<?0.0001) and positive estrogen receptor status (P?=?0.006). Otherwise, the following factors were associated with better relapse-free survival in multivariate analysis: older age (P?=?0.001), never smoking status (P?=?0.021), lower T stage (P?=?0.028), lower lymph node ratio (P?<?0.0001) and positive estrogen receptor status (P?<?0.0001). Early-stage breast cancer patients with a positive smoking history experienced worse relapse-free survival compared to never smokers. Physicians managing breast cancer patients should prioritize discussion about the benefits of smoking cessation when counseling their patients.     

Inflammatory Indexes as Prognostic and Predictive Factors in Ovarian Cancer Treated with Chemotherapy Alone or Together with Bevacizumab. A Multicenter,Retrospective Analysis by the MITO Group (MITO 24)

Background

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking.

Objective

The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab.

Patients and Methods

Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms.

Results

In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p?<?0.0001). In multivariate analyses, the NLR was significantly associated with OS (p?=?0.016), and the PLR was significantly associated with PFS (p?=?0.024). Inflammatory indexes were significantly correlated with patient prognosis in the chemotherapy-alone group (p?<?0.0001). Patients in the chemotherapy with bevacizumab group with a high NLR had a higher PFS and OS (p?=?0.026 and p?=?0.029, respectively) than those in the chemotherapy-alone group. Conversely, PFS and OS were significantly poorer in patients with a high SII (p?=?0.024 and p?=?0.017, respectively).

Conclusion

Our results suggest that bevacizumab improves clinical outcome in patients with a high NLR but may be detrimental in those with a high SII.

     

The Role of Lymphocyte to Monocyte Ratio,Microvessel Density and HiGH CD44 Tumor Cell Expression in Non Hodgkin Lymphomas

Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC >2.6 in DLBCL and ALC/AMC?≥?4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p?<?0.05). In DLBCL, MVD?>?42 blood vessels/0.36 mm² correlated with primary resistant disease (p?<?0.0001), poorer EFS and OS (p?=?0.014). High CD44s expression in FL correlated with inferior EFS and OS (p?<?0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51–7.09, p?=?0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08–1.79, p?=?0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17–23.21, p?=?0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06–14.95, p?=?0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s).     

Strong Correlation Between mRNA Expression Levels of HIF-2α, VEGFR1, VEGFR2 and MMP2 in Laryngeal Carcinoma

The hypoxia that arises due to the rapid proliferation of tumor cells is a fundamental driving force for the canonical pathway of neovascularization. In the current study we report a very strong correlation between mRNA expression levels of HIF-2α (but not HIF-1α), VEGFR-1, VEGFR-2 and MMP2 in ex vivo samples from laryngeal carcinoma. Sixty-three samples from patients with histopathologically verified carcinoma of the larynx were examined in this study. Total RNA was isolated from both normal and tumor fresh frozen tissues of each patient and real-time quantitative PCR reactions were performed. The mRNA expression levels of HIF-1α, HIF-2α, VEGFR1, VEGFR2 and MMP2 were acquired. We found strong positive correlations between mRNA expression levels of HIF-2α and VEGFR-1, r _s (98)?=?.671, p?<?.0005; HIF-2α and VEGFR-2, r _s (98)?=?.742, p?<?.0005; HIF-2α and MMP2, r _s (98)?=?.566, p?<?.0005; VEGFR-1 and VEGFR-2, r _s (98)?=?.791, p?<?.0005; VEGFR-1 and MMP2, r _s (98)?=?.709, p?<?.0005; VEGFR-2 and MMP2, r _s (98)?=?.793, p?<?.0005. Our results provide evidence for the regulatory connection between HIF-2α and VEGFR-1, VEGFR-2 and MMP2 in the light of ETS1/ HIF-2α regulatory axis on a non-in-vitro level in carcinoma tissue, uncover some of the differences between the homologues HIF-1α and HIF-2α and round up and support the results from different experimental models in this field.     

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P?=?0.006, P?=?0.037, and P?=?0.003, respectively) and longer OS (P?<?0.001, P?=?0.02, and P?<?0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR)?=?3.1; P?=?0.007]and death (HR?=?6.4; P?<?0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.