The role of adjuvant chemotherapy for patients with resected pancreatic cancer: Systematic review of randomized controlled trials and meta-analysis

Background: In patients undergoing surgery for resectable pancreatic cancer prognosis still remains poor. The role of adjuvant treatment strategies (including chemotherapy and chemoradiotherapy) following resection of pancreatic cancer remains controversial. Methods: A Medline-based literature search was undertaken to identify randomized controlled trials that evaluated adjuvant chemotherapy after complete macroscopic resection for cancer of the exocrine pancreas. Five trials of adjuvant chemotherapy were eligible and critically reviewed for this article. A meta-analysis (based on published data) was performed with survival (median survival time and 5-year survival rate) being the primary endpoint. Results: For the meta-analysis, 482 patients were allocated to the chemotherapy group and 469 patients to the control group. The meta-analysis estimate for prolongation of median survival time for patients in the chemotherapy group was 3 months (95% CI 0.3-5.7 months, p = 0.03). The difference in 5-year survival rate was estimated with 3.1% between the chemotherapy and the control group (95% CI -4.6 to 10.8%, p > 10.05). Conclusion: Currently available data from randomized trials indicate that adjuvant chemotherapy after resection of pancreatic cancer may substantially prolong disease-free survival and cause a moderate increase in overall survival. In the current meta-analysis, a significant survival benefit was only seen with regard to median survival, but not for the 5-year survival rate. The optimal chemotherapy regimen in the adjuvant setting as well as individualized treatment strategies (also including modern chemoradiotherapy regimens) still remain to be defined. Copyright (C) 2008 S. Karger AG, Basel

Bridge-Pier Caisson foundations subjected to normal and thrust faulting:physical experiments versus numerical analysis

Surface fault ruptures can inflict serious damage to engineering structures built on or near them. In the earthquakes of Kocaeli, Chi-chi, and Wenchuan a number of bridges were crossed by the emerging normal or thrust faults suffering various degrees of damage. While piles have proved incapable of tolerating large displacements, massive embedded caisson foundations can be advantageous thanks to their rigidity. The paper explores the key mechanisms affecting the response of such bridge foundations subjected to dip-slip (normal or thrust) faulting. A series of physical model experiments are conducted in the National Technical University of Athens, to gain a deeper insight in the mechanics of the problem. The position of the caisson relative to the fault rupture is parametrically investigated. High-resolution images of the deformed physical model is PIV-processed to compute caisson displacements and soil deformation. A novel laser scanning technique, applied after each dislocation increment, reveals the surface topography (the relief) of the deformed ground. 3D finite element analyses accounting for soil strain-softening give results in accord with the physical model tests. It is shown that the caisson offers a kinematic constraint, diverting the fault rupture towards one or both of its sides. Depending on the caisson's exact location relative to the rupture, various interesting interaction mechanisms develop, including bifurcation of the rupture path and diffusion of plastic deformation.</p

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma

Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy

BACKGROUND: Advanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy. METHODS: The aim of this prospective multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients. Primary endpoint is the incidence of clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and / or pelvic and / or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission at 3, 6, 9 and 12 months, overall survival and bleeding. Trial registration: isrctn.org identifier CCT-NAPN-16752, controlled-trials.com identifier: ISRCTN02140505. RESULTS: An interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding (5 pts vs. 6 pts, Chi2: 0.763). CONCLUSIONS: PROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer. Its results will lead to a new understanding of the role of heparins in the prevention of venous thromboembolism and of their effect on survival, remission rates and toxicity of chemotherapeutic regimens

Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study

Gemcitabine and oxaliplatin (GEMOX) are active as first-line therapy against advanced pancreatic cancer. This study aims to evaluate the activity and tolerability of this combination in patients refractory to standard gemcitabine (GEM). A total of 33 patients (median age of 57) were included with locally advanced and metastatic evaluable diseases, who had progressed during or following GEM therapy. The GEMOX regimen consisted of 1000 mg m−2 of GEM at a 100-min infusion on day 1, followed on day 2 by 100 mg m−2 of oxaliplatin at a 2-h infusion; a cycle that was given every 2 weeks. All patients received at least one cycle of GEMOX (median 5; range 1–29). Response by 31 evaluable patients was as follows: PR: 7/31(22.6%), s.d. ⩾8 weeks: 11/31(35.5%), s.d. <8 weeks: 1/31(3.2%), PD: 12/31(38.7%). Median duration of response and TTP were 4.5 and 4.2 months, respectively. Median survival was 6 months (range 0.5–21). Clinical benefit response was observed in 17/31 patients (54.8%). Grade III/IV non-neurologic toxicities occurred in 12/33 patients (36.3%), and grade I, II, and III neuropathy in 17(51%), 3(9%), and 4(12%) patients, respectively. GEMOX is a well-tolerated, active regimen that may provide a benefit to patients with advanced pancreatic cancer after progression following standard gemcitabine treatment

The ‘ins and outs’ of colonoscopy at Wits Donald Gordon Medical Centre, South Africa: A practice audit of the outpatient endoscopy unit

Background. In South Africa, there are no national guidelines for the conduct or quality assessment of colonoscopy, the gold standard for investigation and diagnosis of bowel pathology.Objectives. To describe the clinical profile of patients and evaluate the practice of colonoscopy using procedural quality indicators at the Wits Donald Gordon Medical Centre (WDGMC) outpatient endoscopy unit (OEU).Methods. We conducted a prospective, clinical practice audit of colonoscopies performed on adults (≥18 years of age). A total of 1 643 patients were included in the study and variables that were collected enabled the assessment of adequacy of bowel preparation, length of withdrawal time and calculation of caecal intubation rate (CIR), polyp detection rate (PDR) and adenoma detection rate (ADR). We stratified PDR and ADR by sex, age, population group, withdrawal time and bowel preparation. CIR, PDR and ADR estimates were compared between patient groups by the χ2 test; Fisher’s exact test was used for 2 × 2 tables. A p-value &lt;0.05 was used. Benchmark recommendations by the American Society for Gastrointestinal Endoscopy (ASGE)/American College of Gastroenterology (ACG) Task Force on Colorectal Cancer (CRC) were used in this audit to assess individual endoscopist performance and that of the endoscopy unit as a whole.Results. The mean age of patients was 55.7 (standard deviation (SD) 14.4; range 18 - 91) years, ~60% were female, and the majority (75.5%) were white. Of the outpatients, 77.6% had adequate bowel preparation (ASGE/ACG benchmark ≥85%). The CIR was 97.0% overall, and screening colonoscopy was 96.3% (ASGE/ACG benchmark ≥90% overall and ≥95% for screening colonoscopies). The median withdrawal time for negative-result screening colonoscopies was 5.7 minutes (interquartile range (IQR) 4.2 - 9.3; range 1.1 - 20.6) (ASGE/ACG benchmark ≥ 6minutes), and PDR and ADR were 27.6% and 15.6%, respectively (ASGE/ACG benchmark ADR ≥25%). We demonstrated a 23.7% increase in PDR and 14.1% increase in ADR between scopes that had mean withdrawal times of ≥6 minutes and &lt;6 minutes, respectively. Although the number of black Africans in the study was relatively small, our results showed that they have similar ADRs and PDRs to the white population group, contradicting popular belief.Conclusions. The WDGMC OEU performed reasonably well against the international guidelines, despite some inadequacy in bowel preparation and lower than recommended median withdrawal times on negative-result colonoscopy. Annual auditing of clinical practice and availability of these data in the public domain will become standard of care, making this audit a baseline for longitudinal observation, assessing the impact of interventions, and contributing to the development of local guidelines

Skin cancers in albinos in a teaching Hospital in eastern Nigeria - presentation and challenges of care

<p>Abstract</p> <p>Background</p> <p>Albinism is a genetic disorder characterized by lack of skin pigmentation. It has a worldwide distribution but is commoner in areas close to the equator like Nigeria. Skin cancers are a major risk associated with albinism and are thought to be a major cause of death in African albinos. Challenges faced in the care of these patients need to be highlighted in order to develop a holistic management approach with a significant public health impact. The aim of the study was to determine the pattern of skin cancers seen in Albinos, and to highlight problems encountered in their management.</p> <p>Method</p> <p>Case records of albinos managed in Imo state University teaching Hospital from June 2007 to May 2009 were reviewed. The data obtained was analyzed using descriptive statistics.</p> <p>Results and discussion</p> <p>In the period under review, albinos accounted for 67% of patients managed for primary skin cancers. There were twenty patients with thirty eight (38) lesions. Sixty one percent of the patients were below 40 years. Average duration of symptoms at presentation was 26 months. The commonest reason for late presentation was the lack of funds. Squamous cell carcinoma was the commonest histologic variant. Most patients were unable to complete treatment due to lack of funds.</p> <p>Conclusion</p> <p>Albinism appears to be the most important risk factor in the development of skin cancers in our environment. Late presentation and poor rate of completion of treatment due to poverty are major challenges.</p

Parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study

<p>Abstract</p> <p>Background</p> <p>Cachexia is a common problem in patients (pts) suffering from upper gastrointestinal cancer. In addition, most of these patients suffer from malabsorption and stenosis of the gastrointestinal tract due to their illness. Various methods of supplementary nutrition (enteral, parenteral) are practised. In patients with advanced pancreatic cancer (APC), phase angle, determined by bio-electrical impedance analysis (BIA), seems to be a survival predictor. The positive influence of BIA determinate predictors by additional nutrition is currently under discussion.</p> <p>Methods</p> <p>To examine the impact of additional parenteral nutrition (APN) we assessed outpatients suffering from APC and progressive cachexia. The assessment based on the BIA method. Assessment parameters were phase angle, ECM/BCM index (ratio of extracellular mass to body cell mass), and BMI (body mass index). Patients suffering from progressive weight loss in spite of additional enteral nutritional support were eligible for the study.</p> <p>Results</p> <p>Median treatment duration in 32 pts was 18 [8-35] weeks. Response evaluation showed a benefit in 27 pts (84%) in at least one parameter. 14 pts (43.7%) improved or stabilised in all three parameters. The median ECM/BCM index was 1.7 [1.11-3.14] at start of APN and improved down to 1.5 [1.12-3.36] during therapy. The median BMI increased from 19.7 [14.4-25.9] to 20.5 [15.4-25.0]. The median phase angle improved by 10% from 3.6 [2.3-5.1] to 3.9 [2.2-5.1].</p> <p>Conclusions</p> <p>We demonstrated the positive impact of APN on the assessed parameters, first of all the phase angle, and we observed at least a temporary benefit or stabilisation of the nutritional status in the majority of the investigated patients. Based on these findings we are currently investigating the impact of APN on survival in a larger patient cohort.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00919659</p

Adaptation of the WHO AWaRe (Access, Watch, Reserve) antibiotic classification to support national antimicrobial stewardship priorities in the UK: findings from a modified Delphi approach to achieve expert consensus

Objectives: In 2017, the WHO introduced the AWaRe (Access, Watch and Reserve) classification of antibiotics to support antibiotic stewardship (AMS) at local, national and global levels. We assessed the categorization of each of the antibiotics for systemic use for antimicrobial stewardship and quality improvement practice across primary and secondary care in the UK, proposing a nationally adapted UK-AWaRe classification. Methods: A four-stage modified Delphi survey was conducted to review the AWaRe classifications in light of antibiotic resistance profiles, antibiotic use and stewardship practice in the UK. Recommendations were iteratively discussed and consensus reached on how to adapt the WHO AWaRe list. Implications of the proposed new categorization for possible antibiotic usage targets were assessed using England national antibiotic consumption data as a case study. Results: Sixty-one experts across the four UK nations participated in the modified Delphi process. Consensus was most easily reached, with least between-expert variation, for Access antibiotics. Seventeen antibiotics differed in categorization when comparing proposed adapted UK-AWaRe classification and the 2023 WHO AWaRe classification. Through the focus group discussions, the importance of clear messaging was highlighted for the proposed move of first-generation cephalosporins into the Access category, a step-change from the 2019 England AWaRe classification, where all cephalosporins were in the Watch category. From the case study analysis of national data in England, Access antibiotics accounted for >60% of human antibiotic use between 2018 and 2022, 69.7% when using the WHO 2023 classification and 63.7% with the proposed UK-adapted 2024 classification. Conclusions: An adapted UK-AWaRe list has been suggested through a consensus-reaching process. This will support national AMS and antibiotic usage targets of the UK antimicrobial resistance 2024–29 national action plan

A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer

Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients