Long-term Treatment Outcomes In Patients Research Articles

RESECTION OF TRACHEAL BIFURCATION IN TREATMENT OF NON-SMALL CELL LUNG CANCER (LITERATURE REVIEW)

Over the past few years, significant advances in surgical and anesthetic techniques as well as appropriate selection of patients have led to an improvement in the immediate and long-term treatment outcomes in patients with non-small cell lung cancer with involvement of tracheal bifurcation. In accordance with the current selection criteria, patients with contralateral lymph node metastases (lung root, aortic window, paratracheal area) require chemotherapy or chemoradiotherapy with subsequent estimation of follow-up and treatment strategy. Surgeries with resection of tracheobronchial bifurcation are considered technically complicated, and they should be performed in carefully selected lung cancer patients and only in specialized centers with extensive experience. It allows the incidence of intra-and postoperative complications to be significantly reduced.

Transanal endorectal stepwise gradient muscular cuff cutting pull-through method: Technique refinements and comparison with laparoscopy-assisted procedures.

In all existing radical resection procedures available for Hirschprung's disease (HD), the muscular cuff has been retained. In recent years, our study group has modified the procedure using a stepwise gradient muscular cuff cutting pull-through method for the treatment of HD. The objective of the present study was to assess patient prognosis following the use of the transanal endorectal pull-through (TEPT) method or the laparoscopy-assisted pull-through (LPT) method and to provide evidence to assist in clinical decisions. The medical records of 172 patients (age, ≥3 years) who underwent TEPT or LPT for HD between September 2003 and August 2014 at the Pediatric Surgery Department of The Affiliated Hospital of Zunyi Medical College (Zunyi, China) were reviewed (TEPT, n=94; LPT, n=78). Preoperative, intraoperative and post-operative data for the subjects involved were recorded. Each patient's family was interviewed using a uniform 12-item post-pull-through long-term outcome questionnaire, which was scored in order to compare the short and long-term treatment outcomes of patients in each group. Patients in the LPT group had significantly prolonged operating times, reduced intraoperative blood loss and perioperative transfusion rates and shorter anal dissection times. Furthermore, the oral feeding time and length of hospital stay were similar between groups. There were no significant differences in early complications between the groups. No significant differences in late complications, including anastomotic stricture and enterocolitis were observed; however, the soiling and constipation rates were significantly higher in the TEPT group compared with the LPT group. The stool pattern score was not significantly different between groups, while the frequency of bowel movements in the LPT group was significantly higher compared with the TEPT group from 9-24 months post-surgery. The stepwise gradient muscular cuff cutting pull-through method demonstrated a good safety profile and efficacy with regard to the long-term outcomes of patients with HD. These results support the clinical application of LPT as a promising surgical approach for children with HD.

Analysis of sparing surgical procedures use in breast cancer patients at the Oncology Centre in Bydgoszcz in 2002–2017

Introduction. Diagnosis of breast cancer at its early stage influences significantly long-term treatment outcomes in patients. As result, more often application of breast-conserving surgical procedures becomes possible. This paper presents our centre’s up-to-date experiences in this field. Materials and methods. 12,337 patients diagnosed with primary malignant neoplasm of the breast surgically treated at the Oncology Centre in Bydgoszcz between 2002 and 2017. Analysis of applied breast-conserving procedures in the analysed group. Results. Observation of consecutive years indicates over double increase in the number of patients (498 in 2002, 1136 in 2017). Breast-conservative treatment (BCT) was recorded in 10.6% of patients (2002) and 65.1% in 2017. Treatment sparing lymph nodes of the axillary fossa concerned 2.2–79.0% in the analyzed period. Conclusions. In the analyzed time period, we recorded a significant increase in the number of surgical BCT procedures applied. It was possible due to regular introduction of changes regarding diagnostic and therapeutic algorithms to our everyday clinical practice in patients suffering from malignant breast neoplasms.

ROLE OF LAPAROSCOPY IN THE TREATMENT OF ENDOMETRIAL CANCER IN WOMEN OVER 70 YEARS OF AGE

Surgery remains the main method of treatment for endometrial cancer (EC). Treatment of elderly and senile patients is particularly difficult due to the high prevalence of comorbidities in this population and large number of intraand postoperative complications that can potentially occur. The article compares laparoscopic and laparotomic approaches in surgical treatment of patients with EC. We analyzed clinical and morphological features of EC, characteristics of intraoperative and postoperative periods, complications and long-term treatment outcomes in patients treated at the N.N. Petrov Research Institute of Oncology.

Tüylü Hücreli Lösemili Hastaların Uzun Dönem Tedavi Sonuçları: Tek Merkez Deneyimi

Amaç: Tüylü hücreli lösemi (THL) kemik iliği, periferik kan, dalak, karaciğer ve lenf nodlarının çevresel sitoplazmik uzantılı malign B hücrelerin infiltrasyonu ile karakterize klonal B hücre hastalığıdır. Kladribin ve pentostatin gibi pürin analogları öncesinde ortalama yaşam süresi 4 yıl iken, sonrasında bu süre 15 yıla kadar yükselmiştir. Bu makalede kliniğimizde takip edilen THL'li hastaların klinik özellikleri ve tedavi sonuçlarını değerlendirmeyi amaçladık. Gereç ve Yöntemler: Karadeniz Teknik Üniversitesi Tıp Fakültesi Hematoloji Bilim Dalında Ekim 2007 ile Haziran 2015 yılları arasında THL tanısı konulan ve kladribin alan hastaların klinik özellikleri ve tedavi sonuçları retrospektif olarak değerlendirildi. Bulgular: 16 hastanın 15'i erkek ve 1'i kadın olup ortanca tanı yaşı 54 (35-75) yıl idi. Kladribin ile 15 hastada (%94) tam hematolojik yanıt (THY), 1 hastada (%6) parsiyel yanıt (PY) gözlendi. Sekiz hastada (%50) relaps gelişti ve ortalama progresyonsuz yaşam süresi 78 ay idi. Hastaların relaps anındaki yaş ve komorbid durumları değerlendirildiğinde 4 hastaya tek ajan rituksimab, 2 hastaya kladribin uygulandı ve 5 hastada (%83) THY, 1 hastada (%17) PY izlendi. Ardından 3 hastada (%50) 2. relaps izlenmiş olup ortalama progresyonsuz yaşam süresi 54.7 ay idi. Tüm hastaların ortalama yaşam süresi 105 ay, 8 yıllık ortalama yaşam oranı %66 idi. Sonuç: Kladribinin THL?de etkin ve güvenli bir tedavi seçeneği olduğu, relaps gelişiminde kladribin için uygun olmayan hastalarda rituksimab kullanılabileceği ve uygun vakalarda birlikte kullanımının tedavi etkinliğini artırabileceği kanaatine varıldı.

Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs

A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. This longitudinal observational cohort study was conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. A total of 1795 individuals who were newly treated for epilepsy with AEDs between July 1, 1982, and October 31, 2012, were included in this analysis. All patients were followed up for a minimum of 2 years (until October 31, 2014) or until death, whichever came sooner. Data analysis was completed between March 2015 and May 2016. Treatment with antiepileptic drugs for patients newly diagnosed with epilepsy. Seizure control was assessed at the end of the study period. Probability of achieving 1-year seizure freedom was estimated for each AED regimen prescribed. Multivariable models assessed the associations between risk factors and AED treatment outcome after adjustments were made for demographic and clinical characteristics. Of the 1795 included patients, 964 (53.7%) were male; the median age was 33 years (range, 9-93 years). At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer. Among those achieving 1-year seizure freedom, 993 (86.8%) were taking monotherapy and 1028 (89.9%) had achieved seizure control with the first or second AED regimens. Of the total patient pool, 906 (50.5%) remained seizure free for 1 year or longer with the initial AED. If this AED failed, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen (odds ratio, 1.73; 95% CI, 1.56-1.91; P < .001). Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled.

Treatment Outcome of Obstructive Colorectal Cancer With Bowel Perforation

The objective of this study was to analyze the short- and long-term treatment outcomes of patients with bowel perforation caused by obstructive colorectal cancer. From April 2003 to March 2013, 15 patients with bowel perforation caused by obstructive colorectal cancer underwent emergency surgery at our hospital. Clinical outcomes were retrospectively analyzed by age, sex, tumor location, tumor stage, preoperative APACHE II severity score, time to surgery from diagnosis, operative method, and postoperative complications. We studied short-term outcomes and long-term prognosis by overall survival. Ten men and 5 women, with a median age of 67.6 years, were enrolled in the study. The mortality rate was 20%, and the median APACHE II score was 15. The 11 patients who survived had significantly lower APACHE II scores than the 4 fatal cases (P = 0.02). Excluding the patient with stage IV cancer, the median overall survival was 18.9 months. Five patients (50%) had recurrence and distant metastasis. APACHE II score may be a useful predictive marker for short-term outcome and determining operative method in patients with bowel perforation caused by obstructive colorectal cancer. Perforation should be considered as a high-risk factor for cancer recurrence, most of which are peritoneal.

Individual surgical tactics in the treatment of chronic pancreatitis and pancreatic pseudocysts

Authors present the results of own surgical treatment of patients with chronic pancreatitis (CP) and its complications. The article analyzes the effectiveness of the treatment of these patients aimed at the developing individual surgical tactics. Based on the CP causes and its clinical manifestations analysis, the author proved and formulated the absolute and relative indications for surgical interventions. Authors attract attention to the careful attitude to pancreatic tissues and other surgical operations, which are intended to preserve the pancreatic blood supply throughout the postoperative period, efficient abdominal cavity drainage, etc. — everything refers to the maximal prevention of postoperative complications. The evaluation of the long-term treatment outcomes in patients with CP has detected the maximal (71.2 %) prevalence of good and insignificant predominance (7.9 %) of poor results of surgical treatment.

Californium-252 neutron brachytherapy combined with external pelvic radiotherapy plus concurrent chemotherapy for cervical cancer: a retrospective clinical study

BackgroundCervical cancer is the sixth most common cancer in Chinese women. A standard treatment modality for cervical cancer is the combination of surgery, chemotherapy, external-beam radiotherapy and intracavitary brachytherapy. The aim of this study was to retrospectively assess the long-term treatment outcomes of patients with cervical cancer who were treated with californium-252 neutron brachytherapy combined with external-beam radiotherapy plus concurrent chemotherapy.MethodsWe retrospectively analyzed the medical records of 150 patients with primary stages IB-IVB cervical cancer who received neutron brachytherapy combined with external-beam radiotherapy concurrently with cisplatin chemotherapy. All patients were followed up. Using an actuarial analysis, patient outcomes and treatment-related adverse effects were evaluated and compared.ResultsThe median overall survival (OS) was 33.2 months. The 3-year progression-free survival rates for patients with stages I–II, III, and IV diseases were 81.0% (68/84), 65.0% (39/60), and 0% (0/6), respectively; the 3-year OS rates were 90.5% (76/84), 85.0% (51/60), and 16.7% (1/6), respectively. Vaginal bleeding was controlled within the median time of 4.0 days. One month after treatment, 97.3% of patients achieved short-term local control. The local recurrence rates for patients with stages I–II, III, and IV disease were 4.8% (4/84), 11.7% (7/60), and 33.3% (2/6), respectively, and the occurrence rates of distant metastasis were 16.7% (14/84), 25.0% (15/60), and 100.0% (6/6), respectively. Cancer stage, tumor size, and lymph node metastasis were identified as prognostic risk factors, but only lymph node metastasis was found to be an independent prognostic factor. The most common adverse effects during treatment were grades 1 and 2 irradiation-related proctitis and radiocystitis.ConclusionFor patients with cervical cancer, neutron brachytherapy combined with external-beam radiotherapy plus concurrent chemotherapy produces a rapid response and greatly improves local control and long-term survival rates with tolerable adverse effects.

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

Clinical outcomes of EUS-guided drainage of debris-containing pancreatic pseudocysts: a large multicenter study.

Background and study aims Data on clinical outcomes of endoscopic drainage of debris-free pseudocysts (PDF) versus pseudocysts containing solid debris (PSD) are very limited. The aims of this study were to compare treatment outcomes between patients with PDF vs. PSD undergoing endoscopic ultrasound (EUS)-guided drainage via transmural stents. Patients and methods Retrospective review of 142 consecutive patients with pseudocysts who underwent EUS-guided transmural drainage (TM) from 2008 to 2014 at 15 academic centers in the United States. Main outcome measures included TM technical success, treatment outcomes (symptomatic and radiologic resolution), need for endoscopic re-intervention at follow-up, and adverse events (AEs). Results TM was performed in 90 patients with PDF and 52 with PSD. Technical success: PDF 87 (96.7 %) vs. PSD 51 (98.1 %). There was no difference in the rates for endoscopic re-intervention (5.5 % in PDF vs. 11.5 % in PSD; P = 0.33) or AEs (12.2 % in PDF vs. 19.2 % in PSD; P = 0.33). Median long-term follow-up after stent removal was 297 days (interquartile range [IQR]: 59 – 424 days) for PDF and 326 days (IQR: 180 – 448 days) for PSD (P = 0.88). There was a higher rate of short-term radiologic resolution of PDF (45; 66.2 %) vs. PSD (21; 51.2 %) (OR = 0.30; 95 % CI: 0.13 – 0.72; P = 0.009). There was no difference in long-term symptomatic resolution (PDF: 70.4 % vs. PSD: 66.7 %; P = 0.72) or radiologic resolution (PDF: 68.9 % vs. PSD: 78.6 %; P = 0.72) Conclusions There was no difference in need for endoscopic re-intervention, AEs or long-term treatment outcomes in patients with PDF vs. PSD undergoing EUS-guided drainage with transmural stents. Based on these results, the presence of solid debris in pancreatic fluid collections does not appear to be associated with a poorer outcome.

Treatment with high doses of pegvisomant in 56 patients with acromegaly: experience from ACROSTUDY.

To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I. ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the 'high'-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35-60 (10-90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the 'low'-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3-10 (10-90%)). Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m(2)). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups. Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

The impact of ERAS strategy implementation on long-term treatment outcomes in patients with stage III and high-risk stage II colorectal cancer

Objectives: Patients with stage III and high-risk stage II colorectal cancer (CRC) require both curative surgery and adjuvant chemotherapy (ACT). Though ERAS strategy influences the optimal timing and total amount of patients undergoing ACT, evidence clarifying the impact of ERAS on oncologic outcomes is lacking. Methods: Between 2008 and 2014, 330 patients with primary resectable stage II-III CRC were enrolled in the ERAS arm (N=130) and traditional care (TC) arm (N=200). Results: Overall postoperative grade II-IV complications (PCs) rate was 7.8% and 21.6% for ERAS and TC arm (p<0.01), grade V – 1 (0.8%) vs. 7 (3.5%) (p<0.05). All patients who did not have PCs showed significant OS benefit – 85.8±4.1% and 81.7±4.5% vs. 53.3±17% and 45.7±9.6% (p<0.05). In the ERAS arm, 87 patients (67%) started ACT in optimal terms: within 4 weeks (w) - 66 (51%), 8w – 21 (16%). 29 (22%) failed to undergo ACT and 14 (11%) had ≥8 week delay. In the TC arm, 104 (52%) failed, 30 (15%) had no delay, 30 (15%) – 4 week delay, and 36 (18%) – ≥8 week delay. Multivariate analysis in the ERAS arm had confirmed PCs as an independent prognostic factor for delay of ACT ≥ 4 weeks (p=0.029, HR=0.399), but not failure; in TC arm – both delay and failure. In the ERAS arm, 3-year OS had no significant difference for those who underwent ACT within 4 and 8 weeks – 72.3±12.2% and 58.3±10.2% (p=0.320). However, patients with no-use and ≥8 week delay had significantly worse OS and DFS rates (29.6±32.2% and 30.5±26.8%) compared with ACT start within 4 weeks (p=0.023). No significant difference in the TC arm was observed in OS for those who started ACT within 4-8 weeks and with ≥8 week delay (64.2±19%, 52.5±20%, 46.1±9%), however, a time-dependent trend towards OS and DFS improvement was noticeable. No use of ACT was strongly associated with poor OS (18.2±16%). No significant difference in DFS was observed in both groups, except for no-use of ACT. Cox regression analysis defined ≥8 week delay and no-use of ACT as independent risk factor for OS and DFS deterioration (p<0.001, HR=1.639) in ERAS arm and PCs (p=0.021, HR=0.615) – in TC arm. Conclusion: ERAS strategy had a significant impact on long-term treatment outcomes for stage III and high-risk stage II CRC. Disclosure of interest: None declared.

IMMEDIATE RESPONSE TO NEOADJUVANT CHEMOTHERAPY INCLUDING CAPECITABINE AND LONG-TERM TREATMENT OUTCOMES OF OPERABLE BREAST CANCER

The present study was undertaken to determine the relationship between tumor response to neoadjuvant chemotherapy including capecitabine and long-term treatment outcomes in patients with operable breast cancer. material and methods. The study included 139 patients with stage T2-3N0-2M0 breast cancer, who received 2-4 courses of neoadjuvant chemotherapy with the FAC and САХ regimens. Immediate response was assessed using the RECIST criteria. Long-term treatment outcomes and metastasis-free survival rates were evaluated using the Kaplan-Meier method. Results. By assessing the relationship between long-term treatment outcomes and the immediate response to adjuvant chemotherapy with capecitabine, we identified the group of patients with tumor regression ≥ 80%, who had the 7-year metastasis-free survival rates similar to those observed in patients with pathologic complete response. Such factors as the primary tumor size, regional tumor spread, receptor status of tumor tissue and the number of chemotherapy courses were found to have no impact on the frequency of hematogenous metastasis. Conclusion. The results obtained indicate that ≥ 80% tumor regression after neoadjuvanch chemotherapy including capecitabine can be considered as a predictive parameter for assessing metastasis-free survival in patients with operable breast cancer.

Four Weeks Administration Schedule of Ropeginterferon Alfa-2b (AOP2014/P1101) in Polycythemia Very Patients Allows Maintaining of Efficacy with Favorable Toxicity Profile in the Phase I/II Peginvera Stud

Four Weeks Administration Schedule of Ropeginterferon Alfa-2b (AOP2014/P1101) in Polycythemia Very Patients Allows Maintaining of Efficacy with Favorable Toxicity Profile in the Phase I/II Peginvera Stud

Long Term Efficacy and Safety Results and Analysis of Dose Correlations from the Phase I/II Peginvera Study of Ropeginterferon Alfa-2b, a Novel IFNa-2b, in Polycythemia Vera Patient

Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naive and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct) 400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of 300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlogl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity9s Board of Directors or advisory committees. Zorer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

Catechol-O-methyltransferase (COMT) gene polymorphisms are associated with baseline disability but not long-term treatment outcome in patients with chronic low back pain.

To examine the association between COMT and OPRM1 gene polymorphisms and pain and disability at baseline and long-term follow-up in patients treated for chronic low back pain (LBP). 371 of 767 unrelated European patients recruited from four randomised trials underwent genetic analyses at mean 11.4 years follow-up. 274 patients had fusion and 97 had non-operative treatment. Association analyses included disability, pain, five single nucleotide polymorphisms (SNPs) in the COMT gene, and one SNP in the OPRM1 gene. Analyses were adjusted for age, gender, smoking, analgesics and treatment. Disability at baseline was significantly associated with COMT SNPs rs4818 (p = 0.02), rs6269 (p = 0.007), rs4633 (p = 0.04) rs2075507 (p = 0.009), two haplotypes (p < 0.002), age, gender and smoking (p ≤ 0.002). No significant associations with clinical variables were observed for OPRM1, or for COMT at long-term follow-up. Results suggest that genetic factors are partly responsible for the variation in disability levels in patients presenting with chronic LBP being considered for surgery; in contrast, genetics has no influence on the long-term outcome of treatment.

Switch from Every Two Weeks to Every Four Weeks Administration Schedule of AOP2014, an Innovative Pegylated Interferon Alpha, in Polycythemia Very Patients Allows Maintaining of Efficacy with Improved Toxicity Profile in Phase I/II Study

Background AOP2014 is a next generation long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. Due to this property, reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with Polycythemia Vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development.Study design This phase I/II single arm dose escalation study with cohort extension included 51 patients with PV who could be either cytoreduction therapy naive or pre-treated. AOP2014 was administered subcutaneously in a dose range of 50-540 mcg every two weeks. Main objectives were to define the maximum tolerated dose as well as observe the long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities (results were already presented at the ASH 2013 annual meeting by Gisslinger et al). The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease (by approx. the half) of the overall exposure to the drug. Outcomes of this switch are presented here.Results Patients (period A, median exposure duration 34 weeks, mean monthly dose 484 mcg) were dosed every two weeks based on the Phase II dosing rules prior having switch option. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 413 mcg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for switch. 28 patients (period C, median exposure duration 42 weeks) were then switched to once every four weeks schedule (mean monthly dose 221 mcg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median,% - period A: 43, period B: 43, period C: 42; WBC, median, G/l - period A: 6.1, period B: 5.9, period C: 5.7; platelets, median, G/l - period A: 246, period B: 211, period C: 204). Spleen length stayed stable within the normal range following the switch in the majority of patients either (mean, in cm – period A: 11.4, period B: 8.3, period C: 10.3). Complete response as best individual response could be maintained in 42% from the period A, 55% in the period B and 67% of the period C patients, while for the partial hematological responders the results were 60%, 71% and 67%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 31% of period A patients, compared to 42% of period B and 75% of period C patients. Decrease of application frequency and total dose exposure led to decrease of the occurrence of all/drug related AEs (measured as mean count of adverse events [AE] per patient week exposure) to 0.17/0.09 (arm A) from 0.3/0.09 (arm B) and 0.08/0.03 (arm C).Conclusions This explorative data from endpoints pre-defined in the prospective study demonstrate the feasibility to further reduce the frequency of AOP2014 administration to once every four weeks in responding patients, previously treated every two weeks. Reduced injection frequency is not associated with a lack of- response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon exposure rather than dose of interferon is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which is continuously maintained at lower AOP2014 levels. DisclosuresGisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Kadlecova:AOP Orphan Pharmaceuticals AG: Consultancy. Zagrijtschuk:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

Predictive factors of depression and its therapy

Predictive factors of for the occurrence of depressive episodes include psychosocial and biological risk factors. These factors reflect the heterogeneity and complexity of the disease. They can identify groups that would benefit from preventive measures and provide indications for suitable preventive strategies. In recent decades considerable scientific effort, for example in the field of psychiatric genetics, has been undertaken to identify predictive factors for individual antidepressant therapy response and as an aid for individual treatment decisions. However, no clinically usable conclusions could yet be drawn from the respective findings. In practice clinical factors, such as symptom cluster of the depressive disorder and specific properties of the antidepressant, individual factors and contextual factors, such as the type of treatment facility, decision support and economic aspects, are factors influencing the choice of a specific antidepressant. Early clinical improvement under antidepressant medication in the first 2 weeks of treatment is one of the best predictors for the long-term treatment outcome in patients with major depressive disorder.

Remote Results of Intraarterial Chemotherapy with Local Hyperthermia in the Treatment of Patients with Nasal and Paranasal Sinuses Cancer

ABSTRACT Aim: To study remote results and the role of intraarterial chemotherapy with local hyperthermia in the treatment of nasal and paranasal sinus cancer patients. Methods: 209 patients were treated over the period 2000 - 2008. T3 stage was diagnosed in 106 patients (51.4%) and T4 stage in 103 (48.6%) patients. Squamous cell carcinoma was found in 71.3% patients. Patients were divided into 4 groups: 1) intraarterial chemotherapy with local hyperthermia and radiotherapy (58 patients; 2) intraarterial chemotherapy and radiotherapy (48 patients;, 3) systemic chemotherapy and radiotherapy (58 patients); 4) radiotherapy followed by surgery (45 patients). We used the following regimen: cisplatin 100 mg, fluorouracil 3000 mg and doxorubicin 60 mg. In 1st group 58 patients received local UHF–hyperthermia with the frequency of 40 MHz increasing the temperature up to 41-43°C in the tumour. Patients of the 1st and 2nd groups, received intraarterial chemotherapy with ligation and catheterization of external carotid artery. All patients received telegammatherapy, dose 40-60 Gy. For appreciating of the remote results SPSS-16 statistical methods were used. Results: Continuous regional intraarterial chemical induction in the background of local hyperthermia significantly increased the results of treatment. Surgical treatment was made to 128 (61.2%) patients at second grade of complex therapy. In the 1st group of patients 3-year survival rate was 83.4%, and 5-year survival rate was 73.0%. In the 2nd group those rates were 80.4% and 66.7%, respectively. In the 3rd group those rates were 68.2% and 60.6%, respectively. In the 4th group those rates were 68.1% and 54.1%, respectively. In the study of long-term treatment outcomes of patients receiving integrated and combined treatment it was found that the recurrence rate in the 1st and 2nd groups compared with the 3rd and 4th groups of patients differed significantly. So in the 1st group these figures were 32.4% in the 2nd group 38.1%, and in the third group recurrence was seen in 45.4% of patients. In the 4th group this figure increased further and was observed in 51.3% of patients. Conclusions: Thus, neoadjuvant continuous intraarterial chemotherapy with local UHF-hyperthermia and radiotherapy in the 1st group of patients allowed us to increase significantly the remote results compared with those in the 3rd group who received systemic chemotherapy. Disclosure: All authors have declared no conflicts of interest.