DNA damage response and potential biomarkers of radiosensitivity in head and neck cancers: clinical implications.

Head and neck cancers include a wide variety of tumor sites that originate in the epithelium of the upper aerodigestive airways. The curative treatment of this group of pathologies most frequently involves multidisciplinary approach in which radiotherapy (RT) plays a central role. Treatment failures are mainly due to recurrences and local or regional evolution and rarely to distant metastases, which emphasizes the importance of ensuring local control. For patients with recurrences, the treatment options are significantly reduced, and prognosis is considerably attenuated. At the cellular level, the main irradiation target is the deoxyribonucleic acid (DNA), its lesions being largely responsible for radiation-induced cell death. However, not all DNA damage will have the same biological significance and a considerable part will be repaired through an intricate network of signaling proteins and repair pathways. Radiobiologically, compared to normal cells, tumor clonogens are defined by malfunction of DNA repair pathways. Tumors with an increased repair capacity, especially DNA double-strand breaks, the most lethal lesions induced by RT, will be radioresistant. The purpose of this review was to elucidate the mechanisms involved in avoiding radiation-induced apoptosis of head and neck cancers mediated by modulating the repair of DNA damage via p53, epidermal growth factor receptor (EGFR) and p16. The role of DNA damage-associated biomarkers in response to irradiation in clinical practice for the selection of personalized treatments and specifying the prognosis and, finally, the bases of immunotherapy association are presented.

Early Deaths in Childhood Cancer in Romania-A Single Institution Study.

(1) Background: Survival in childhood cancer has improved significantly over the last decades. However, early deaths (EDs) represent an important number of preventable deaths. Our aim was to provide more insight intoEDs in developing countries. (2) Methods: We conducted a retrospective analysis of patients aged 0-18 years with childhood cancer diagnosed between 1996 and 2008 and admitted in the Institute of Oncology "Prof. Dr. Ion Chiricuta" Cluj-Napoca (IOCN), Romania. After exclusion of patients (pts) older than 18 years at diagnosis, pts with a missing personal identification number and pts with unconfirmed diagnosis of malignancy, we included 783 pts in the final analysis. We defined ED as survival of less than one month after cancer diagnosis. We divided pts in groups according to age, major tumour categories and treatment time periods. (3) Results: ED was registered in 20 pts (2.55%). A total of 16EDs were registered in haematologic malignancies and 4 in solid tumours. Statistical analysis was performed on pts diagnosed with haematological malignancies. A statistically significant higher proportion of patients with performance status (PS) 3 and 4 died within one month after diagnosis (24.1%) than patients admitted with PS 0-2 (1%)-p < 0.01. We found no statistically significant difference regarding ED when comparing male versus female (p = 0.85), age at diagnosis or between the threeperiods of diagnosis (p = 0.7). (4) Conclusions: PS at admission is an important risk factor associated with ED in pts with haematologic malignancies. ED in our institution reflects frequent late presentation for medical care, late diagnosis and referral to specialised centres.

Genetic predisposition in pediatric oncology.

Identifying patients with a genetic predisposition for developing malignant tumors has a significant impact on both the patient and family. Recognition of genetic predisposition, before diagnosing a malignant pathology, may lead to early diagnosis of a neoplasia. Recognition of a genetic predisposition syndrome after the diagnosis of neoplasia can result in a change of treatment plan, a specific follow-up of adverse treatment effects and, of course, a long-term follow-up focusing on the early detection of a second neoplasia. Responsible for genetic syndromes that predispose individuals to malignant pathology are germline mutations. These mutations are present in all cells of conception, they can be inherited or can occur de novo. Several mechanisms of inheritance are described: Mendelian autosomal dominant, Mendelian autosomal recessive, X-linked patterns, constitutional chromosomal abnormality and non-Mendelian inheritance. In the following review we will present the most important genetic syndromes in pediatric oncology.

Follow-up protocol for oncological patients at risk of developing multiple primary neoplasms.

PURPOSE: Multiple primary neoplasms (MPN) have a growing impact in the outcome of oncological patients given the rising incidence of these entities in daily practice. The early diagnosis of secondary tumors could translate into better survival of patients with MPN. The final objective of this study was the elaboration of a follow-up protocol for oncological patients at risk of developing multiple primary neoplasms. METHODS: Patients with MPN diagnosed and treated in the Oncology Institute "Prof.Dr.Ion Chiricuta" Cluj-Napoca (OICN) between 2008-2012 were included in this nonrandomized, retrospective study and the clinicopathological characteristics of these patients and the prognostic factors possibly involved in the occurrence of MPN were analyzed. RESULTS: 278 patients with MPN were included in this study. The median age at diagnosis was 60 years. The median interval between the diagnosis of the primary and secondary neoplasm was 30.98 months. Smoking and alcohol consumption were the most frequent environmental factors observed in patients with MPN. Patients diagnosed with breast cancers, head and neck cancers, colorectal cancer, prostate cancer, ovarian cancer or uterine body cancer were the patients with the highest risk of developing MPN. CONCLUSION: This first follow-up protocol for oncological patients at risk of developing multiple primary neoplasms could be implemented in daily practice with further validation of the protocol.

Clinical prognostic factors associated with survival and a survival score for patients with brain metastases.

Aim: To identify prognostic factors of survival in patients with brain metastases (BM) and to devise a prognostic score. Patients & methods: In this single-institution retrospective study, we analyzed potential clinical prognostic factors in 1363 patients with BM. Based on the Cox proportional hazard model, we devised a BM score with three classes (score <5, 5-6 and >6). Results: The 1-year overall survival (OS) was 26%. Independent prognostic factors of OS were: age, gender, Karnofski performance status, number of BM, control of primary, presence of extracerebral metastases and type of primary tumor. The 1-year OS was 56% for score <5; 21% for score 5-6 and 4% for score >6 (p < 0.01). Conclusion: The BM score we propose is effective in grouping patients according to their prognosis and can help decision making regarding treatment adjustments.

Survival and quality of life after whole brain radiotherapy with 3D conformal boost in the treatment of brain metastases.

BACKGROUND: Brain metastases are the most frequent intracranial neoplasms in adults. Although overall survival (OS) is an important endpoint in patients receiving radiotherapy, given their poor life expectancy in general, quality of life is becoming an increasingly useful endpoint. Objectives: to evaluate whole brain radiotherapy (WBRT) with 3D conformal boost in brain metastases patients with regard to OS and quality of life. METHODS: During April 2015-May 2017, a total of 35 patients with ≤5, previously untreated, inoperable brain metastases were included prospectively. All patients underwent WBRT followed by 3D conformal boost to the metastatic lesions. EORTC quality of life questionnaires QLQ-C30 and QLQ-BN20 were used at baseline and at end of treatment. The mean initial and final scores were compared using Student test. One-year OS with brain metastases was computed with Kaplan Maier method. RESULTS: Median survival with brain metastases was 4.43 months (0.73-78.53). The one-year OS for patients with one metastasis was 42% versus 15% for more than one (p<0.04). The presence of extracerebral metastases significantly decreased OS from 39% without extracerebral metastases to 19%. (p<0.05). Quality of life improved significantly in several functional domains: physical (48 vs 60.29), role functioning (28.1 vs 44.7), emotional (47.1 vs 80.2), global health status (40.9 vs 62.3). Symptom scores decreased significantly in most items, corresponding to an improvement in the symptom burden: headache (61.9 vs 0.9), nausea and vomiting (45.7 vs 7.1), visual disorder (26.3 vs 9.2), seizures (30.4 vs 0.9), motor dysfunction (46.6 vs 17.1). Symptom scores for fatigue and drowsiness increased significantly (51.1 vs 74.9, respectively 37.1 vs 70.4), indicating worsening of symptoms. CONCLUSIONS: WBRT with 3D conformal boost is a feasible technique which improves quality of life in brain metastases patients. Since survival is limited, the assessment of quality of life is a good indicator of the treatment outcome.

Long-term survival following neoadjuvant chemotherapy and concomitant radiochemotherapy in locally advanced cervical cancer: results of the Oncology Institute "Prof. Dr. Ion Chiricuta" experience.

Objective:to analyze the efficiency of (NACT) followed by concurrent radiochemotherapy (RCT) in patients with locally advanced cervical cancer, 5-year overall, specific and disease-free survival and the prognostic factors correlated with the response and survival. Materials and methods:207 patients with cervical carcinoma stages IIB-IIIB, who received 2-4 cycles of neoadjuvant chemotherapy followed by concurrent chemoradiation were retrospectively analyzed for an objective response (OR), overall survival (OS), and disease-specific survival (DSS) rate. All patients received platinum-based NACT followed by concurrent RCT to a total dose (TD) of 46 Gy/pelvis when patients were evaluated for surgery. Patients with favorable parametrial response optionally underwent surgery. The rest of the patients continued radiochemotherapy exclusively. Results:The baseline characteristics were: median age at diagnosis - 52 years; 82% squamous and 12% adenocarcinoma histologies; 67 patients (32.4%) with FIGO stage IIB, 87 (42%) with stage IIIA and 53 (25.6%) with stage IIIB. The OR rate was 56.5% post-NACT and the complete response (CR) after exclusive RCT was 19.7% while pathological complete response (pCR) in patients that underwent surgery was 61.2%. The median follow-up was 58.3 months. Overall and disease-specific survivals at 5 years were 78% and 84%, respectively. The OS for stages IIB and IIIA was 84%, and 61% for stage IIIB while the DSS rates were 90% for stage IIB, 86% for stage IIIA and 72% for stage IIIB. The disease-free intervals (DFS) rates were 88%, 76% and 69% for stages IIB, IIIA and IIIB, respectively. Conclusions:Neoadjuvant chemotherapy followed by concurrent chemoradiation produces higher response rates and improvements in disease-specific survival and disease-free survival rates compared to RCT.

The impact of multiple primary neoplasms in daily practicea systematic review of the literature.

Multiple primary neoplasms (MPN) represent particular entities with growing impact in our daily practice due to their increasing incidence and implications in the treatment and outcome of oncological patients. MPN have a specific deffinition and can be classified as synchronous or metachronous depending on the time of diagnosis of the first and latter malignancies. We review in this article the possible risk factors involved in the etiology of MPN, the most frequent cancer associations, the incidence of synchronous and metachronous tumors, the stage at diagnosis, the treatment administered to the patients with MPN and the survival of patients with MPN.

Optimizing the use of anti VEGF targeted therapies in patients with metastatic colorectal cancer: review of literature.

Colorectal cancer is one of the most frequent forms of cancer both in men and women, and patients with metastatic disease are now being exposed to an increasing number of therapeutic agents to improve the survival outcomes. Vascular endothelial growth factor (VEGF) has o key role in the tumor growth and spreading. The approval of 4 agents that target angiogenic pathways in combination with standard chemotherapy improve overall and progression free survival and offer many opportunities to sequencing the treatment in patients with metastatic colorectal cancer (mCRC). However, the most effective strategy for the use of these agents remains unclear. This article presents an overview of the actual evidence for the use of agents that target angiogenesis in the treatment of mCRC.

Clinicopathological characteristics of patients with multiple primary neoplasms-a retrospective analysis.

PURPOSE: Multiple primary neoplasms (MPN) represent the occurrence of two or more primary neoplasms in the same individual during lifetime and today there is an increased interest in studying the implications of MPN in the outcome of oncological patients. In this study we aimed to evaluate the clinicopathological characteristics of patients with MPN. METHODS: In this nonrandomized, retrospective study patients with MPN treated in the Oncology Institute "Prof.Dr.Ion Chiricuta" Cluj-Napoca between 2008-2012 were included. Data were collected from the medical charts. RESULTS: 278 patients with MPN were treated in our institute between 2008-2012: 120 patients with synchronous tumors and 158 with metachronous tumors. Of them, 260 patients presented with two MPN and 13 with three MPN. Fifty four percent (n=151) of the patients were females and 127 (46%) males, with a median age at diagnosis of 60 years. Most patients presented with early stage tumors, both for the initial primary tumor (54%) and for the second tumor (55%). The most frequent initial primary tumors were breast, head and neck, colorectal, ovarian, prostate and uterine body cancers and the most frequent second tumors were breast, colorectal, uterine body, head and neck, lung and thyroid cancers. Five-year survival was higher for patients with metachronous tumors (68%) compared with patients with synchronous tumors (54%; p=0.02). CONCLUSION: MPN represent a real challenge in daily practice and their occurrence should not be overlooked. Lack of solid data from the literature makes it difficult to establish which patients are at risk for developing multiple neoplasms and should be closely followed up.

A prospective study of the value of pre- and post-treatment magnetic resonance imaging examinations for advanced cervical cancer.

BACKGROUND AND AIM: Cervical cancer has high incidence and mortality in developing countries. It is the only gynecological malignancy that is clinically staged. Staging at the time of diagnosis is crucial for treatment planning. After radiation therapy, clinical examination is limited because of radiation changes. An imaging method relatively unaffected by radiation changes would be useful for the assessment of therapy results and for management. We sought to demonstrate the value of magnetic resonance imaging (MRI) in the pre- and post-treatment assessment of cervical cancer. METHODS: This was a prospective study, carried out between November 2012 and October 2014 on 18 subjects with advanced-stage cervical cancer diagnosed by colposcopy. The disease stage was determined clinically according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Only patients with disease stage ≥ IIB or IIA with one of the tumor dimensions > 4 cm were enrolled in the study. All patients underwent abdominal-pelvic contrast-enhanced MRI as part of the workup. Tumor size, local invasion, involved pelvic lymph nodes, and staging according to MRI criteria were evaluated. Clinical and MRI examinations were also performed after chemoradiotherapy. After chemoradiotherapy, 94% of the patients (17 of 18) were treated surgically. RESULTS: Eighteen patients aged 32-67 met the inclusion criteria and were enrolled: 10 stage IIB, 6 stage IIIA, 1 stage IIA and 1 stage IIIB, according to clinical staging. Using histopathological findings as a reference, MRI staging accuracy was 83.3%. The concordance of the clinical stage with MRI stage at the first examination was 56%. Parametrial involvement was assessed on pretreatment and post-treatment MRI, with post-treatment MRI compared with histology. There was no statistically significant difference between the pre- and post-therapy gynecological examinations (GYN) and the corresponding MRI assessments as to tumor size measurements (p>0.05). The post-therapy restoration of the cervical stroma ruled out tumor recurrence. CONCLUSIONS: For a detailed characterization of loco-regional extension, the calculation of tumor volume, and the evaluation of distant metastatic changes, clinical examination is insufficient. Magnetic resonance imaging is helpful aftertherapy.

A phase II single institution single arm prospective study with paclitaxel, ifosfamide and cisplatin (TIP) as first-line chemotherapy in high-risk germ cell tumor patients with more than ten years follow-up and retrospective correlation with ERCC1, Topoisomerase 1, 2A, p53 and HER-2 expression.

PURPOSE: One half of high-risk germ cell tumor (HRGCT) patients relapse after standard chemotherapy. This phase II study evaluated prospectively the toxicity and efficacy in first-line of the paclitaxel-ifosfamide-cisplatin combination (TIP) in HRGCT patients and tried to identify biomarkers that may allow patient-tailored treatments. METHODS: Between October 1997- September 2000, 28 chemo-naive HRGCT patients were enrolled. Patients received 4 cycles of TIP (paclitaxel 175 mg/m(2) day 1/; ifosfamide 1.2 g/m(2)/day, days 1-5; Mesna 1.2 g/m(2)/day, days 1-5; and cisplatin 20 mg/m(2)/day, days 1-5 every 3 weeks). A non-randomized comparison was made between HRGCT patients treated in the same period with first-line TIP and bleomycin-etoposide-cisplatin (BEP) (28 patients vs 20). In 17 HRGCT patients treated between 1998-2006, ERCC1, Topoisomerase 1 and 2A, p53 and HER-2 expression was retrospectively analysed by immunohistochemistry (IHC) (7 patients with TIP, 10 with BEP), and correlations were made with response to chemotherapy and survival. RESULTS: With a median follow-up of 72 months [range 48+...89+], 5-year disease free survival (DFS) was 55%, with 95% CI 36-72, and the overall survival (OS) was 63%, with 95% CI 44-78. In June 2015, with a median follow-up of 196.47 months (range 177.30-209.27) (>15 years), 12 [%?] patients were alive and disease-free, and 16 [%?] had died (12 specific causes). There was no significant correlation between the expression of ERCC1, Topoisomerase 1 and 2A, HER-2 and p53 and response to treatment. CONCLUSION: Long-term follow-up showed no difference in OS between TIP vs BEP as first-line therapy. Both regimens had mild toxicity.

Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of a third-generation chemotherapy regimen in the adjuvant setting to radically operated patients with gastric cancer. This proposed new adjuvant regimen was also compared with a consecutive retrospective cohort of patients treated with the classic McDonald regimen. METHODS: Starting in 2006, a non-randomized prospective phase II study was conducted at the Institute of Oncology of Cluj-Napoca on 40 patients with stage IB-IV radically resected gastric adenocarcinoma. These patients were administered a chemotherapy regimen already considered to be standard treatment in the metastatic setting: ECX (epirubicin, cisplatin, xeloda) and were compared to a retrospective control group consisting of 54 patients, treated between 2001 and 2006 according to McDonald's trial. RESULTS: In a previous paper, we reported toxicities and the possible predictive factors for these toxicities; in the present article, we report on the results concerning predictive factors on overall survival (OS) and disease free survival (DFS). The proposed ECX treatment was not less effective than the standard suggested by McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage was an independent prognostic factor for OS and DFS. N ratio >70% was an independent predictive factor for OS and locoregional disease control. The resection margins were independent prognostic factors for OS and DFS. CONCLUSION: The proposed treatment is not less effective compared with the McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage represented an independent prognostic factor and N ratio >70% was a predictive factor for OS and DFS. The resection margins were proven to be independent prognostic factors for OS and DFS.

Circulating tumor cells in germ cell tumors: are those biomarkers of real prognostic value? A review.

Analysis of circulating tumor cells from patients with different types of cancer is nowadays a fascinating new tool of research and their number is proven to be useful as a prognostic factor in metastatic breast, colon and prostate cancer patients. Studies are going beyond enumeration, exploring the circulating tumor cells to better understand the mechanisms of tumorigenesis, invasion and metastasis and their value for characterization, prognosis and tailoring of treatment. Few studies investigated the prognostic significance of circulating tumor cells in germ cell tumors. In this review, we examine the possible significance of the detection of circulating tumor cells in this setting.

Multimodal endocavitary ultrasound versus MRI and clinical findings in pre- and post-treatment advanced cervical cancer. Preliminary report.

AIMS: The aim of this study was to evaluate the use of pre and post-therapy transrectal and transvaginal ultrasonography (TRUS, TVUS) with contrast enhancement and strain elastography compared with clinical examination and magnetic resonance imaging (MRI) in the assessment of advanced stage cervical cancer. MATERIAL AND METHODS: This was a prospective study, carried out over a period of nine months on subjects with advanced-stage cervical cancer (stage >/= IIB). All included patients were examined clinically and underwent abdomino-pelvic contrast enhanced MRI and multimodal US examinations (TRUS with strain elastography and contrast enhanced TVUS) at the time of diagnosis and after radiochemotherapy. Tumor size and staging at TRUS and TVUS was compared with the same data obtained by clinical examination and MRI. Pathology was the golden standard. RESULTS: Eight patients accomplished the inclusion criteria. In five cases the tumor stage was identical on clinical and MRI examinations. In all cases parametrial infiltration was diagnosed by all pre-treatment examinations. No significant differences were observed in tumor size between clinical, US and MRI exams either at baseline or post-therapy, in native or post-contrast examinations. The size of the tumor evaluated pre-treatment proved to be significantly smaller post-contrast in both US and MRI examinations compared with the native images. Post-therapy, no significant differences were observed on US measured tumor dimensions when comparing native with post-contrast images. Oppositely, significant smaller dimensions were observed on post-contrast MRI compared with native scans. CONCLUSIONS: TRUS is accurate in the estimation of pre-therapy cervical cancer dimension. The post therapy tumor evaluation is better performed with MRI. The use of intravenous contrast agents on both examinations did not improved the accuracy of tumor evaluation pre or post-therapy.

Classic tumor markers in gastric cancer. Current standards and limitations.

The progress made in the last few years made available a large amount of information that needs to be integrated and ordered by oncologists. Tumor markers are one of the pieces that physicians need to fit into the bigger puzzle. This article will detail the most frequent etiologies for the surges in the carcinoembryonic antigen (CEA), cancer-related antigen 72-4 (CA 72-4), cancer-related antigen 19-9 (CA 19-9) serum levels and their indications. Although tumor markers are an invaluable asset to medical practice, their role in screening, diagnosis and oncologic treatment remains poorly standardized. Ongoing or future clinical trials will shed light on pending problems.

Local experience in cervical cancer imaging: Comparison in tumour assessment between TRUS and MRI.

OBJECTIVE: The aim of study was to analyze the accuracy of TRUS (transrectal ultrasound) vs. MRI (magnetic resonance imaging) and clinical gynecological examination estimation in the evaluation of tumor dimensions. METHODS: The patients inclusion criterion included primarily pathologically squamous cell carcinoma, but excluded were patients who had not undergone BT (brachytherapy) and treated with palliative intent. We offer two types of treatment for locally advanced cervical cancer: (a) radiochemotherapy followed by surgery and (b) exclusive radiochemotherapy. Imaging tests follow the presence of tumor and tumor size (width and thickness). Each examination was performed by a different physician who had no knowledge of the others' findings. All patients underwent MRI prior to EBRT (external beam radiation therapy) while 18 of them also at the time of the first brachytherapy application. For the analysis we used the r-Pearson correlation coefficient. RESULTS: In 2013, 26 patients with cervical cancer were included. A total of 44 gynecological examinations were performed, 44 MRIs and 18 TRUSs. For the comparisons prior to EBRT the correlation coefficient between TRUS vs. MRI was r = 0.79 for AP and r = 0.83 for LL, for GYN vs. MRI was r = 0.6 for AP and r = 0.75 for LL. Prior to BT for GYN vs. MRI, r values were 0.60 and 0.63 for AP and LL, respectively; for GYN vs. TRUS, r values were 0.56 and 0.78 for AP and LL, respectively. CONCLUSIONS: A high correlation between the three examinations was obtained. As such, TRUS can be considered a suitable method in the evaluation of tumor dimensions.

Neoadjuvant conformal chemoradiation with induction chemotherapy for rectal adenocarcinoma. A prospective observational study.

BACKGROUND & AIMS: The purpose of this prospective observational study was to evaluate the rate and the prognostic factors for down-staging and complete response for rectal adenocarcinoma after induction chemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphincter-saving surgery. METHODS: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2-4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy. RESULTS: The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p<0.01), cN0 (p<0.01), distance from anal verge >5 cm (p<0.01), initial CEA <6.2 ng/ml (p<0.01), higher number of chemotherapy cycles with Oxaliplatin (pROC=0.05) and protraction of radiotherapy of >35 days (p<0.01). Nine patients from 81 (11.1%) presented complete response (7 pathological and 2 clinical); the independent prognostic factors were stage cT2 versus cT3-4 (p<0.01), initial tumor size ≤3.5 cm and distance from anal verge >5 cm (p=0.03). Sixty-eight patients (79.1%) underwent radical surgery and among them 35 patients (51.5 %) had a sphincter saving procedure. CONCLUSIONS: Induction chemotherapy with neoadjuvant chemoradiation produced important down-staging in rectal adenocarcinoma. Independent prognostic factors for T down-staging were: age, cN0, distance from anal verge, initial CEA, the number of Oxaliplatin cycles and duration of radiotherapy; for complete response: cT2, initial tumor size and distance from the anal verge.

Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure.

BACKGROUND: Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. METHODS: Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient's 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest. RESULTS: A 2859-gene signature was identified to distinguish between responder and non-responder patients. 'DNA Replication, Recombination and Repair' represented one of the most important mechanisms activated in non-responsive cervical tumors, and the 'Role of BRCA1 in DNA Damage Response' was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples. CONCLUSIONS: Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure.

A new score predicting survival prognosis after whole-brain radiotherapy alone for brain metastases in elderly patients.

BACKGROUND/AIM: Elderly patients represent an important subgroup of patients with brain metastases. A survival score has been developed specifically for these patients. PATIENTS AND METHODS: A total of 544 elderly patients (aged ≥65 years) receiving whole-brain radiotherapy alone were divided into a test (n=272) and a validation group (n=272). In the multivariate analysis of the test group, survival was significantly associated with gender, performance status, and number of organs involved by extracranial metastases. These factors were included in the score. Total scores representing the sum of the three factor scores were 3-13 points. Four prognostic groups were formed. RESULTS: The 6-month survival rates were 2% for those with 3-6 points, 17% for those with 7-9 points, 56% for those with 10-12 points and 90% for those with 13 points in the test group (p<0.001), and 4%, 21%, 50% and 86%, respectively, in the validation group (p<0.001). CONCLUSION: This score is reproducible and helps estimate the survival prognosis of elderly patients with brain metastasis.