Beta Blockers with Statins May Decrease All-Cause Mortality in Patients with Cardiovascular Diseases and Locally Advanced Unresectable Non-Small-Cell Lung Cancer after Chemoradiotherapy.

The study was conducted in the era when maintenance immunotherapy with durvalumab was not available in clinical practice after chemoradiotherapy (CRT) in unresectable non-small-cell lung cancer (NSCLC). The main aim of the study was to check whether the presence of cardiovascular diseases (CVD) and their pharmacotherapy affects the overall survival (OS) in such NSCLC patients undergoing sequential CRT. The group of 196 patients were analyzed: 101 patients with CVD (51.53%) and 95 patients with other reasons of qualification for sequential CRT (decreased performance status, older age, and other non-cardiovascular co-morbidities). Although patients with CVD were more often in older age, and they more often experienced cardiac and nephrological complications (p < 0.05 for all), there was a statistically nonsignificant trend for lower all-cause mortality in patients with CVD. The lowest all-cause mortality was observed in patients treated with beta-blockers and statins after two (HR = 0.31; 95%CI: 0.1-0.98; p = 0.047), three (HR = 0.33; 95%CI: 0.13-0.81; p = 0.015) and even four (HR = 0.45; 95%CI: 0.22-0.97; p = 0.027) years of follow-up. The benefit in OS remained significant in 101 patients with CVD treated with beta-blockers (HR = 0.65; 95%CI: 0.43-0.99; p = 0.045), and eventually statin, throughout the whole follow-up (log-rank p < 0.05). Further prospective studies are necessary to confirm the role of beta-blockers and statins in reduction of mortality in NSCLC patients undergoing radical CRT.

Performance-Status Deterioration during Sequential Chemo-Radiotherapy as a Predictive Factor in Locally Advanced Non-Small Cell Lung Cancer.

The role of sequential chemoradiotherapy in non-small cell lung cancer (NSCLC) patients who are not eligible for concurrent therapy has not been clearly defined. The aim of this study was to determine the usefulness of Karnofsky performance status (KPS) monitoring and to define the factors determining clinical deterioration during sequential chemoradiotherapy in patients treated from July 2009 to October 2014. The study included 196 patients. The clinical stage was defined as III A in 94 patients (48%) and III B in 102 patients (52%). Reduced KPS was found in 129 patients (65.8%). Baseline KPS had no significant prognostic significance. Deterioration of KPS during chemoradiotherapy was observed in 53 patients (27%) and had a negative predictive value for both worse-progression free survival (HR = 1.44; 95% CI: 1.03-1.99; p = 0.03) and overall survival (HR = 1.42; 95% CI: 1.02-1, 99; p = 0.04). The deterioration of KPS correlated with the disease control rate 6 weeks after the end of chemoradiotherapy (p = 0.0085). The risk of KPS worsening increased with each subsequent day between the end of chemotherapy and the start of radiotherapy (OR = 1.03; 95%CI: 1.01-1.05; p = 0.001), but decreased with each year of older age of patients (OR = 0.94, 95% CI: 0.9-0.98, p = 0.009). The time between the end of chemotherapy and the start of radiotherapy determined the prognosis of NSCLC after chemoradiotherapy. It should be adjusted to the age of patients.

Elderly Patients with Locally Advanced and Unresectable Non-Small-Cell Lung Cancer May Benefit from Sequential Chemoradiotherapy.

Concurrent chemoradiotherapy is recommended for locally advanced and unresectable non-small-cell lung cancer (NSCLC), but radiotherapy alone may be used in patients that are ineligible for combined-modality therapy due to poor performance status or comorbidities, which may concern elderly patients in particular. The best candidates for sequential chemoradiotherapy remain undefined. The purpose of the study was to determine the importance of a patients' age during qualification for sequential chemoradiotherapy. The study enrolled 196 patients. Older patients (age > 65years) more often had above the median Charlson Comorbidity Index CCI > 4 (p < 0.01) and Simplified Charlson Comorbidity Index SCCI > 8 (p = 0.03), and less frequently the optimal Karnofsky Performance Score KPS = 100 (p < 0.01). There were no significant differences in histological diagnoses, frequency of stage IIIA/IIIB, weight loss, or severity of smoking between older and younger patients. Older patients experienced complete response more often (p = 0.01) and distant metastases less frequently (p = 0.03). Univariable analysis revealed as significant for overall survival: age > 65years (HR = 0.66; p = 0.02), stage IIIA (HR = 0.68; p = 0.01), weight loss > 10% (HR = 1.61; p = 0.04). Multivariable analysis confirmed age > 65years as a uniquely favorable prognostic factor (HR = 0.54; p < 0.01) independent of lung cancer disease characteristics, KPS = 100, CCI > 4, SCCI > 8. Sequential chemoradiotherapy may be considered as favorable in elderly populations.

Thymic epithelial tumors: Do we know all the prognostic factors?

BACKGROUND: Thymic epithelial tumors constitute a morphologically and clinically diverse group of rare neoplasm of the anterior mediastinum. METHODS: Here, we present an analysis of 188 patients diagnosed with primary thymic tumors between 1995 and 2015. The prognostic value of selected clinical and morphological factors was assessed in relation to overall survival and recurrence-free survival. RESULTS: The risk of recurrence increased significantly in thymic carcinoma diagnosis (P = 0.0036), co-occurrence of other diseases, and weight loss (P = 0.0012 and 0.0348, respectively). Multivariate analysis showed that the most important independent risk factor for disease recurrence was clinical stage IV (P = 0.0036). A total of 63 patients (33.5%) died. In the univariate analysis, the following factors were considered as independent prognostic factors for overall survival: clinical stage (P < 0.0001), histological type (P < 0.0001), lymph node involvement (P < 0.001), WHO performance status 2 (P < 0.0001), anemia (Hb <9.5 g/dL; P = 0.0002), leucocytosis (>12.5 G/L; P = 0.0011), LDH level (>185 U/L; P < 0.0001), concomitant diseases (P = 0.0012) and weight loss (P < 0.0001).The strongest independent risk factor for death was stage IV disease (P < 0.001). CONCLUSIONS: The results confirmed a fairly good prognosis for patients with thymic epithelial tumors. Clinical stage was the most important prognostic factor, but, some additional clinical factors may also have prognostic value.

Stereotactic radiotherapy of the tumor bed compared to whole brain radiotherapy after surgery of single brain metastasis: Results from a randomized trial.

PURPOSE: To evaluate if neurological/cognitive function outcomes in patients with resected single brain metastasis (BM) after stereotactic radiotherapy of the tumor bed (SRT-TB) are not inferior compared to those achieved with whole-brain radiotherapy (WBRT). METHODS: Patients with total/subtotal resection of single BM were randomly assigned either to SRT-TB (n=29) or WBRT (n=30). SRT-TB arm consisted of 15Gy/1 fraction, or 5×5Gy. WBRT consisted of 30Gy/10 fractions. Neurological/cognitive failure was defined as a decrease of neurological score by one point or more, or a worsening of the MiniMental test by at least 3 points, or neurological death. Cumulative incidence of neurological/cognitive failure (CINCF), neurological death (CIND), and overall survival (OS) were compared. RESULTS: Median follow-up was 29months (range: 8-45) for 15 patients still alive. The difference in the probability of CINCF at 6months (primary endpoint) was -8% in favor of WBRT (95% confidence interval: +17% -35%; non-inferiority margin: -20%). In the intention-to-treat analysis, two-year CIND rates were 66% vs. 31%, for SRT-TB and WBRT arm, respectively, p=.015. The corresponding figures for OS were 10% vs. 37%, p=.046. CONCLUSIONS: Non-inferiority of SRT-TB was not demonstrated in our underpowered study. More data from randomized studies are needed for confirmation of the value of this method.

Application of plasma circulating microRNA-448, 506, 4316, and 4478 analysis for non-invasive diagnosis of lung cancer.

Aberrant expression of microRNAs (miRNAs) in cancer patients compared to healthy people as well as possibility of detection of these molecules in blood samples make them potential biomarkers of various cancers. In the present study, we investigated the potential role of four miRNAs as lung cancer (LC) biomarkers: miRNA-448, 506, 4316, and 4478. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) technique, we assessed expression of studied miRNAs in plasma samples of 90 lung cancer patients and 85 healthy individuals. Receiver operating curves (ROC) with area under the curve (AUC) were used to assess accuracy of studied miRNAs for distinguishing LC patients from healthy individuals. The miRNA-448 and 4478 were significantly overexpressed in lung cancer patients compared to healthy people and these two molecules were qualified for further analysis. Combination ROC analysis of both biomarkers reached 90 % of sensitivity and 76.3 % of specificity (AUC = 0.896) for distinguishing operable (stage IA-IIB) non-small cell lung cancer (NSCLC) patients from healthy subjects. Our results suggest that the examination of miRNAs could be considered as potential lung cancer, non-invasive biomarkers.

Plasma circulating microRNA-944 and microRNA-3662 as potential histologic type-specific early lung cancer biomarkers.

Altered expression of microRNAs (miRNAs) is associated with the development and invasion of cancers by regulating post-transcriptionally gene function. Possibility of detection of miRNA expression in patients' plasma or serum makes them valuable biomarkers of different neoplasms. In the present study, we investigated the potential role of miR-944 and miR-3662 expression analysis as novel lung cancer biomarkers and their lung tumor specificity in plasma samples of 90 patients with lung cancer and 85 healthy individuals using quantitative reverse transcription-polymerase chain reaction analysis. Expression of miR-944 and miR-3662 was upregulated in patients with lung cancer in comparison with healthy individuals. Receiver operating curve analysis has presented diagnostic power of analysis of both miRNA expressions for detection of patients with I and II stages of non-small cell lung cancer with area under the curve (AUC) of 0.881. Moreover, miR-944 has shown diagnostic accuracy for operable squamous cell carcinoma detection (AUC = 0.982), whereas miR-3662 has shown the diagnostic accuracy for operable adenocarcinoma (AUC = 0.926). Higher stage of lung cancer correlated with higher miRNA expressions. Our results suggest that the profile of studied miRNAs could be further evaluated and considered as potential lung cancer biomarkers.

[AMP-activated protein kinase (AMPK) as therapeutic target]. / Kinaza bialkowa aktywowana przez AMP (AMPK) jako cel terapeutyczny.

AMP-activated protein kinase (AMPK) is one of the major energy sensor at both: cellular and whole body level. It exists as heterotrimer containing three subunits: the catalytic α subunit, ß and regulatory γ. AMPK is localized both in the cytoplasm and in the nucleus. It is activated by increasing concentrations of AMP during the energy shortage, causing activation of catabolic pathways and inhibition of energy consuming processes. AMPK activity can be regulated allosterically: by binding AMP to a regulatory γ subunit, as well as by phosphorylation on Thr172 of the catalytic α subunit by other kinases. Activated AMPK can effectively inhibit the mTOR pathway which is hyperactive in many types of cancer. On the other hand AMPK inactivation associates with the type II diabetes, diet-induced obesity, insulin resistance and the development of other metabolic disorders. The AMPK dysfunction is also observed in inflammation. It was discovered during last years that abnormalities in the AMPK function can induce the metabolic reprogramming in cancer cells known as the Warburg effect. Additionally, AMPK is activated during irradiation. Its activation leads to inhibition of growth. On the other hand, active AMPK enables cells to survive in difficult conditions such as hypoxia, or glucose deprivation. Because of its crucial role in maintaining of the energy homeostasis AMPK is an excellent therapeutic target. However, it still remains unknown what is better: to activate or inhibit the AMPK function.

Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study.

PURPOSE: To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. METHODS: Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. RESULTS: 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. CONCLUSIONS: The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

Patterns of failure after postoperative radiotherapy for incompletely resected (R1) non-small cell lung cancer: implications for radiation target volume design.

OBJECTIVE: Overall survival (OS) and pattern of failure in R1-resected non-small cell lung cancer (NSCLC) patients treated with 3D-planned postoperative radiotherapy (PORT) was retrospectively evaluated. The outcomes and patterns of failure in patients with (+) and without (-) extracapsular nodal extension (ECE) were compared and analyzed with respect to the radiation target volume design. MATERIALS AND METHODS: Eighty R1-resected (37 ECE+ and 43 ECE-) patients received PORT (60Gy, 2Gy daily) between 2002 and 2011. Patients with N2 disease received limited elective nodal irradiation (ENI); for pN0-1 disease the use of ENI was optional. Among ECE- (extranodal-R1) patients there were 35 pN0-1 and eight pN2 cases; in pN0-1 patients, patterns of failure and outcomes were analyzed with respect to the use of ENI. Loco-regional failure (LRF) was defined as in-field relapse; isolated nodal failure (INF) was defined as out-of-field regional nodal recurrence occurring without LRF, irrespective of distant metastases. RESULTS: The actuarial 3-year OS rate was 36.3% (median: 30 months). Three-year OS rates in the ECE- and ECE+ group were 40.4% and 31.4%, with median OS of 31 and 24 months, respectively (p=0.43). In multivariate analysis, the presence of ECE was correlated with OS (HR=3.02; 95% CI: 1.00-9.16; p=0.05). Three-year cumulative incidence of LRF (CILRF) was 14.5% and 15.5% in the ECE- and ECE+ groups, respectively (p=0.98). Three-year cumulative incidence of INF (CIINF) was 14.1% in the ECE- group and 11.1% in the ECE+ group (p=0.76). For pN0-1 patients treated with and without ENI (13 and 22 patients) 3-year CILRF rates were 7.7% and 20.8%, respectively (p=0.20); 3-year CIINF rates were 9.1% and 16.3%, respectively (p=0.65). CONCLUSION: PORT resulted in a relatively good survival of R1-resected NSCLC patients. Relatively high incidence of INF was found in both ECE+ and ECE- patients. For ECE+ patients, treated with limited ENI, distant failure remains a major concern, so the design of ENI fields seems of lesser importance. Omission of ENI in pN0-1 (extranodal-R1) patients resulted in an unacceptably high incidence of INF. We postulate the use of some form of ENI in this setting.

Palliative thoracic radiotherapy for lung cancer.

Despite an increasing use of chemotherapy in the palliative setting for lung cancer, the role of palliative thoracic radiotherapy should not be disregarded. It offers quick and efficient palliation, with improvement observed in approximately two-thirds of treated patients. There is evidence that the short and long radiotherapy schedules are equally effective for poor performance patients. Higher radiation doses delivered via protracted schedules give a modest survival benefit for good performance patients. The current review covers the issues related to the use of palliative thoracic radiotherapy, such as total dose, fractionation, delayed versus immediate use, external-beam radiotherapy versus endobronchial brachytherapy, combination with chemotherapy, re-irradiation and palliation with radiation in small-cell lung cancer.

The quality of pathological reports of postoperative specimens in rectal cancer: an audit from the Mazovia region.

BACKGROUND: Recently, pathologists have recommended new standards of post operative specimen evaluation in rectal cancer. These new standards include: macroscopic assessment of the quality of surgical excision of mesorectum, microscopic measurement of circumferential resection margin and the assessment of at least 12 mesorectal lymph nodes regarding the presence of metastases. The purpose of our study was to find out whether those standards have been implemented into a routine practice in Poland. MATERIAL AND METHODS: This is a retrospective evaluation of pathological reports of postoperative specimens in 51 consecutive rectal cancer patients who were referred to our institution from 19 hospitals for postoperative chemoradiation between January 2006 and December 2007. Items were audited in pathological reports that were mentioned in the background. RESULTS: Only 14% of pathological reports included the macroscopic assessment of the quality of surgical excision of mesorectum and 57% reported microscopic measurement of circumferential resection margin. The median number of retrieved lymph nodes was 9, with a range between 0 and 36. CONCLUSION: The quality of pathological reports was unsatisfactory. Actions should be taken on a national level to improve the current situation. There is an urgent need for providing pathologists with adequate guidelines.