Use of Different Anti-PD-1 Checkpoint Combination Strategies for First-Line Advanced NSCLC Treatment-The Experience of Ion Chiricuța Oncology Institute.

PURPOSE: Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuța Oncology Institute. METHODS: A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors. RESULTS: Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months (p = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months (p = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% (p = 0.22). Older age, impaired PS (2 versus 0-1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2). CONCLUSIONS: Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials.

Unselective Measurement of Tumor-to-Stroma Proportion in Colon Cancer at the Invasion Front-An Elusive Prognostic Factor: Original Patient Data and Review of the Literature.

The tumor-to-stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study, we proposed confirming or dismissing the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma < 10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients, had stroma-rich tumors, 4% had stroma-poor tumors and 89.2% had tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease-specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation between stroma proportion and tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

Prognostic Factors Influencing Survival and a Treatment Pattern Analysis of Conventional Palliative Radiotherapy for Patients with Bone Metastases.

BACKGROUND: Treatment indication for bone metastases is influenced by patient prognosis. Single-fraction radiotherapy (SFRT) was proven equally effective as multiple fractionation regimens (MFRT) but continues to be underused. OBJECTIVE: Primary objectives: (a) to identify prognostic factors for overall survival and (b) to analyze treatment patterns of palliative radiotherapy (proportion of SFRT indication and predictive factors of radiotherapy regimen) for bone metastases. METHODS: 582 patients with bone metastases who underwent conventional radiotherapy between January 1st 2014-31 December 2017 were analyzed. The Cox proportional hazard model was used to identify predictors of overall survival. For the treatment pattern analysis, 677 radiotherapy courses were evaluated. The logistic regression model was used to identify potential predictors of radiotherapy regimen. RESULTS: The 3-year overall survival was 15%. Prognostic factors associated with poor overall survival were multiple bone metastases [hazard ratio (HR = 5.4)], poor performance status (HR = 1.5) and brain metastases (HR = 1.37). SFRT prescription increased from 41% in 2017 to 51% in 2017. Predictors of SFRT prescription were a poor performance status [odds ratio (OR = 0.55)], lung (OR = 0.49) and urologic primaries (OR = 0.33) and the half-body lower site of irradiation (OR = 0.59). Spinal metastases were more likely to receive MFRT (OR = 2.09). CONCLUSIONS: Based on the prognostic factors we identified, a selection protocol for patients candidates for palliative radiotherapy to bone metastases could be established, in order to further increase SFRT prescription in our institution.

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.

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.

Rare tumors: A comprehensive analysis of cancer.

PURPOSE: To evaluate differences between the data from project "Surveillance of Rare Cancers in Europe" (RARECARENet) and the data from the Institute of Oncology "Prof.Dr. Ion Chiricuta" (IOIC). METHODS: Data from institutional cancer registry of IOIC through 2012 to 2013 and the data published in RARECARENet project were compared. RESULTS: There were 14,127 cases in the IOIC cancer registry but only 13632 were compliant with the RARECARENet categories. Of these 7382 (54%) are common, 5975 (44%) are rare, and 275 (2%) are in the "Other" category compared to RARECARENet (64%, 22%, 14% (p<0.01). From a total of 65 tumor categories, 34 (2.3%) should be given special treatment for rare tumors. Comparing the cases of the IOIC with the data of the RARECARENet project, 14 out of 65 categories show significant structural differences and these represent 81% of our cases. 44.7% of cancers are rare compared to only 22% at the level of the European project (p<0.01). CONCLUSION: Globally, Oncology Institute "Prof.Dr. Ion Chiricuta" receives a large number of rare tumors. There are differences between RARECARENet and IOIC, but these differences are probably due largely to the fact that IOIC receives the largest number of rare tumors from the surrounding area.

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.

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.

Biomarkers for the early detection of relapses in metastatic colorectal cancers.

PURPOSE: To assess prognostic/predictive value of carcinoembryonic antigen (CEA), transthyretin (TRT), αenolase (NNE), ß2-microglobulin (ß2-micro), B-cell activating factor (BAFF) and circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) patients treated with chemotherapy with or without bevacizumab. METHODS: 72 histologically confirmed mCRC patients treated at Oncology Institute Cluj were included. Biomarker levels were measured through validated methods. A manual method was used for CTCs, involving hemolysis, cytospin centrifugation and immunocytochemical staining for pan-cytokeratin. Statistical endpoints were response, progression- free survival (PFS) and overall survival (OS). RESULTS: Initial chemotherapy was fluoropyrimidine/oxaliplatin-based in 93.1%; bevacizumab was added in 58.3% of the patients. Median PFS and OS were 16.4 and 24.4 months. Two-year OS for CR & PR vs SD vs PD were 90% vs 48% vs 12%, respectively (p<0.01). Two-year OS for chemo/ bevacizumab vs chemotherapy: 65% vs 42% (p=0.09). Baseline CEA ≥5 ng/ml had a negative prognostic impact on OS and PFS (p<0.01). High baseline CEA was predictive of improved OS when adding bevacizumab (2-year OS chemo/bevacizumab vs chemo: 60% vs 17%, p<0.01); adding bevacizumab in patients with normal CEA did not improve OS (p=0.29). Higher than cut-off values for TRT had a positive OS prognostic value (p<0.01); higher levels for NNE, ß2-microglobulin and BAFF had a negative impact (p<0.01). Two-year OS for baseline <1 CTC/ml vs ≥1 CTC/ ml was 74% vs 64% respectively (p=0.15). CONCLUSIONS: The evaluated biomarkers could be useful prognostic factors for survival. Baseline CEA also has predictive value, suggesting that patients with low levels do not benefit from bevacizumab. A non-statistically significant correlation was observed between the number of CTCs and outcome.

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.

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.

Determinants of survival after liver resection for metastatic colorectal carcinoma.

PURPOSE: Prognostic factors for survival after liver resection for metastatic colorectal cancer identified up to date are quite inconsistent with a great inter-study variability. In this study we aimed to identify predictors of outcome in our patient population. METHODS: A series of 70 consecutive patients from the oncological hepatobiliary database, who had undergone curative hepatic surgical resection for hepatic metastases of colorectal origin, operated between 2006 and 2011, were identified. At 44.6 months (range 13.7-73), 30 of 70 patients (42.85%) were alive. Patient demographics, primary tumor and liver tumor factors, operative factors, pathologic findings, recurrence patterns, disease-free survival (DFS), overall survival (OS) and cancer-specific survival (CSS) were analyzed. Clinicopathologic variables were tested using univariate and multivariate analyses. RESULTS: The 3-year CSS after first hepatic resection was 54%. Median CSS survival after first hepatic resection was 40.2 months. Median CSS after second hepatic resection was 24.2 months. The 3-year DFS after first hepatic resection was 14%. Median disease free survival after first hepatic resection was 18 months. The 3-year DFS after second hepatic resection was 27% and median DFS after second hepatic resection 12 months. The 30-day mortality and morbidity rate after first hepatic resection was 5.71% and 12.78%, respectively. In univariate analysis CSS was significantly reduced for the following factors: age >53 years, advanced T stage of primary tumor, moderately- poorly differentiated tumor, positive and narrow resection margin, preoperative CEA level >30 ng/ml, DFS <18 months. Perioperative chemotherapy related to metastasectomy showed a trend in improving CSS (p=0.07). Perioperative chemotherapy improved DFS in a statistically significant way (p=0.03). Perioperative chemotherapy and achievement of resection margins beyond 1 mm were the major determinants of both CSS and DFS after first liver resection in multivariate analysis. CONCLUSIONS: In our series predictors of outcome in multivariate analysis were resection margins beyond 1mm and perioperative chemotherapy. Studies on larger population and analyses of additional clinicopathologic factors like genetic markers could contribute to development of clinical scoring models to assess the risk of relapse and survival.

Comparative multivariate analyses of transient otoacoustic emissions and distorsion products in normal and impaired hearing.

BACKGROUND AND AIM: The clinical utility of otoacoustic emissions as a noninvasive objective test of cochlear function has been long studied. Both transient otoacoustic emissions and distorsion products can be used to identify hearing loss, but to what extent they can be used as predictors for hearing loss is still debated. Most studies agree that multivariate analyses have better test performances than univariate analyses. The aim of the study was to determine transient otoacoustic emissions and distorsion products performance in identifying normal and impaired hearing loss, using the pure tone audiogram as a gold standard procedure and different multivariate statistical approaches. METHODS: The study included 105 adult subjects with normal hearing and hearing loss who underwent the same test battery: pure-tone audiometry, tympanometry, otoacoustic emission tests. We chose to use the logistic regression as a multivariate statistical technique. Three logistic regression models were developed to characterize the relations between different risk factors (age, sex, tinnitus, demographic features, cochlear status defined by otoacoustic emissions) and hearing status defined by pure-tone audiometry. The multivariate analyses allow the calculation of the logistic score, which is a combination of the inputs, weighted by coefficients, calculated within the analyses. The accuracy of each model was assessed using receiver operating characteristics curve analysis. We used the logistic score to generate receivers operating curves and to estimate the areas under the curves in order to compare different multivariate analyses. RESULTS: We compared the performance of each otoacoustic emission (transient, distorsion product) using three different multivariate analyses for each ear, when multi-frequency gold standards were used. We demonstrated that all multivariate analyses provided high values of the area under the curve proving the performance of the otoacoustic emissions. Each otoacoustic emission test presented high values of area under the curve, suggesting that implementing a multivariate approach to evaluate the performances of each otoacoustic emission test would serve to increase the accuracy in identifying the normal and impaired ears. We encountered the highest area under the curve value for the combined multivariate analysis suggesting that both otoacoustic emission tests should be used in assessing hearing status. Our multivariate analyses revealed that age is a constant predictor factor of the auditory status for both ears, but the presence of tinnitus was the most important predictor for the hearing level, only for the left ear. Age presented similar coefficients, but tinnitus coefficients, by their high value, produced the highest variations of the logistic scores, only for the left ear group, thus increasing the risk of hearing loss. We did not find gender differences between ears for any otoacoustic emission tests, but studies still debate this question as the results are contradictory. Neither gender, nor environment origin had any predictive value for the hearing status, according to the results of our study. CONCLUSION: Like any other audiological test, using otoacoustic emissions to identify hearing loss is not without error. Even when applying multivariate analysis, perfect test performance is never achieved. Although most studies demonstrated the benefit of using the multivariate analysis, it has not been incorporated into clinical decisions maybe because of the idiosyncratic nature of multivariate solutions or because of the lack of the validation studies.

Tools to identify linear combination of prognostic factors which maximizes area under receiver operator curve.

BACKGROUND: The linear combination of variables is an attractive method in many medical analyses targeting a score to classify patients. In the case of ROC curves the most popular problem is to identify the linear combination which maximizes area under curve (AUC). This problem is complete closed when normality assumptions are met. With no assumption of normality search algorithm are avoided because it is accepted that we have to evaluate AUC n(d) times where n is the number of distinct observation and d is the number of variables. METHODS: For d = 2, using particularities of AUC formula, we described an algorithm which lowered the number of evaluations of AUC from n(2) to n(n-1) + 1. For d > 2 our proposed solution is an approximate method by considering equidistant points on the unit sphere in R(d) where we evaluate AUC. RESULTS: The algorithms were applied to data from our lab to predict response of treatment by a set of molecular markers in cervical cancers patients. In order to evaluate the strength of our algorithms a simulation was added. CONCLUSIONS: In the case of no normality presented algorithms are feasible. For many variables computation time could be increased but acceptable.

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.

Predictors of first recurrence in Clostridium difficile-associated disease. A study of 306 patients hospitalized in a Romanian tertiary referral center.

BACKGROUND & AIMS: Clostridium difficile is recognized as the major cause of nosocomial gastroenteritis usually related to antibiotic treatment. Although treatable, C. difficile--associated disease (CDAD) tends to recur in many patients. The purpose of the study was to analyze the risk factors for recurrence in patients with CDAD after the first treatment with vancomycin, metronidazole or both. METHOD: We conducted a retrospective study of all patients admitted to the Teaching Hospital of Infectious Diseases Cluj-Napoca, Romania, between January 2011 and October 2012 with the diagnosis of CDAD or who developed diarrhoea after admission. A clinical diagnosis was made and culture and toxin A and B detection were carried out. We performed a statistical analysis taking into consideration: age, gender, previous hospital exposure, previous antibiotic treatment, and treatment duration. The patients were followed-up for at least 60 days. RESULTS: We included 306 patients (177 women and 129 men) with a median age of 71 years; 208 patients (68%) had prior hospitalization and 195 (64%) had received prior antibiotic treatment. Actual treatment consisted of vancomycin in 76 (25%) patients, metronidazole in 132 (43%) and both combined in 98 (32%) patients. The average duration of treatment was 10 days. Sixty patients (20%) experienced 95 recurrences and 9 patients died (3%). Treatment with metronidazole, vancomycin or both for 10 or more days did not prevent recurrences. Age over 70 (RR 1.5, CI 95%: 1.055-2.71) and use of PPI (RR 1.3, CI 95%: 1.16-3.1) significantly increased the risk of first recurrence of CDAD. CONCLUSIONS: CDAD recurrence rates were similar to those reported in the literature. The risk of first recurrence was significantly higher in patients older than 70 who also received PPI treatment.

Randomized phase 3 trial comparing 2 cisplatin dose schedules in 326 patients with locally advanced squamous cell cervical carcinoma: long-term follow-up.

OBJECTIVE: The evaluation of 5-year results obtained through 2 radiochemotherapy (RCT) regimens: cisplatin (CDDP), 20 mg/m × 5 days every 21 days; and CDDP, 40 mg/m per week in locally advanced cervical carcinoma. METHODS/MATERIALS: In this single-institution prospective randomized phase 3 study, 326 patients with stage IIB to IIIB squamous cell cervical carcinoma treated from March 2003 to March 2005 were included. One hundred sixty patients (49%) had stage IIB cervical carcinoma, 103 patients (31.5%) had stage IIIA cervical carcinoma, and 63 patients (19.5%) had stage IIIB cervical carcinoma. The patients were randomly assigned to 2 therapeutic arms: 164 patients in arm A (5 days) concurrent RCT with CDDP, 20 mg/m per day, days 1 to 5 every 21 days; and 162 patients in arm B (weekly), concurrent RCT with CDDP, 40 mg/m per day weekly. All patients were treated with external beam radiotherapy on the abdominopelvic region using 15-MV x-rays and a cervical boost using the x-rays arch technique or medium-dose-rate intracavitary brachytherapy. RESULTS: The 5-year survival rate obtained through the 2 RCT regimens are not statistically different, even if a tendency of superiority can be observed in the 5-day arm as far as overall survival (78% in arm A vs 72% in arm B; p = 0.14) and disease-free survival (73% in arm A and 69% in arm B; p = 0.09) are concerned. Five-year local relapse-free survival was significantly superior in the 5-day CDDP arm (87%) in comparison with the weekly CDDP arm (77%); p < 0.01. In the 5-day arm, local relapse rate was twice lower, 21/164 (13%), compared with the weekly arm, 40/162 (25%); p < 0.01). Distance failures were identical in the 2 therapeutic groups: 22/164 (13%) and 21/162 (13%), respectively, which shows the superiority of arm A regarding local control. CONCLUSIONS: The results of our study demonstrate that RCT with cisplatin, 20 mg/m × 5 days every 21 days, is superior regarding local efficacy and is less toxic compared with the weekly chemotherapy regimen.