Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Patterns of Failure Following Dose-escalated Chemoradiotherapy for Fluorodeoxyglucose Positron Emission Tomography Staged Squamous Cell Carcinoma of the Oesophagus.

AIMS: To analyse outcomes and patterns of failure following dose-escalated definitive chemoradiotherapy (CRT) for oesophageal squamous cell carcinoma using fluorodeoxyglucose positron emission tomography for staging and treatment planning. MATERIALS AND METHODS: A retrospective review of patients with oesophageal squamous cell carcinoma receiving definitive CRT to a dose of ≥56 Gy was conducted. Patient and tumour characteristics, treatment received and first sites of relapse were analysed. RESULTS: Between 2003 and 2014, 72 patients were treated with CRT to a median dose of 60 Gy (range 56-66 Gy). The median age was 63 years; most (61%) were stage III/IVa. The median follow-up was 57 months. Three year in-field control, relapse-free survival and overall survival was 64% (95% confidence interval 50-75%), 38% (95% confidence interval 27-50%) and 42% (95% confidence interval 30-53%), respectively. Of the 41 failures prior to death or at last follow-up date, isolated locoregional relapse occurred in 16 patients (22%) with isolated in-field recurrence in 11 patients (15%). Distant failure as first site of relapse was present in 25 patients (35%). No in-field failures occurred in the 11 patients with cT1-2, N0-1 tumours. The median survival for cT4 tumours was 8 months, with five of eight patients developing local progression within the first 6 months. CONCLUSIONS: Dose-escalated radiotherapy was associated with promising rates of in-field local control, with the exception of cT4 tumours. Distant failure remains a significant competing risk. Our data supports the need for current trials re-examining the role of dose escalation in the modern era.

Regional radiotherapy may improve outcomes in patients with early stage breast cancer undergoing breast conservation therapy.

BACKGROUND: Breast conservation therapy (BCT) is recommended as standard management of early breast cancer. The aim of this study was to retrospectively evaluate the results of BCT to identify prognostic factors predictive of treatment outcomes. PATIENTS AND METHODS: Four hundred and ninety-eight eligible women with unilateral stage I-II breast cancer who had undergone BCT were analyzed. RESULTS: The cumulative incidence of local recurrence (LR) was 1.9% and 3.7% at 3- and 5-years respectively. The 5-year disease-free, cancer-specific, and overall survival (DFS, CSS, OS) were 80.0%, 87.3% and 85.4% respectively. Significant independent predictors for LR included young age and absence of chemotherapy. Regional nodal radiotherapy was significantly associated with improved DFS and OS. CONCLUSION: Our results confirmed the efficacy of BCT in the treatment of early breast cancer and indicated that inclusion of regional nodal areas within the radiotherapy field might be beneficial in the BCT setting, particularly for patients with adverse risk features.

Inhibition of adherence of mucoid Pseudomonas aeruginosa by alginase, specific monoclonal antibodies, and antibiotics.

The adherence of pseudomonal species was investigated by using a newly developed radiometric dacron fiber microcolumn assay. Pseudomonas aeruginosa, P. stutzeri, and Xanthomonas maltophilia were more adherent (approximately 20%) than P. pseudomallei, P. fluorescens, and P. cepacia (approximately 10%). Mucoid strains of P. aeruginosa were consistently more adherent than nonmucoid strains (30% versus 20%). Alginase was shown to inhibit the adherence of mucoid but not nonmucoid P. aeruginosa. Monoclonal antibodies to alginate were also shown to inhibit the adherence of mucoid but not nonmucoid P. aeruginosa. In addition, antibiotics active against P. aeruginosa were shown to inhibit the adherence of both mucoid and nonmucoid strains. Furthermore, synergism between dyadic combinations of monoclonal antibodies and antibiotic (ciprofloxacin), as well as alginase and antibiotic, was also observed. These results indicate that bacterial alginate has an intrinsic role in the adherence of mucoid P. aeruginosa and may have evolved not only for protection against dehydration in the water and soil ecosystem of this bacterium, but also as a means of attaching to soil substrates in the same ecosystem to enhance survival. They also suggest that synergistic combinations of antibiotics with alginase or monoclonal antibodies to alginate may be of value in the therapy of some pseudomonal infections.

Suppression of lymphocyte and neutrophil functions by Pseudomonas aeruginosa mucoid exopolysaccharide (alginate): reversal by physicochemical, alginase, and specific monoclonal antibody treatments.

The mucoid exopolysaccharide (MEP or alginate) of Pseudomonas aeruginosa is thought to be a virulence factor for this organism by virtue of its ability to suppress local host defense mechanisms. We purified MEP from clinical isolates of mucoid P. aeruginosa, subjected it to degradation by ultrasonication, heat, alkali, and alginase, and reacted it with monoclonal antibodies specific for MEP epitopes. Partial reversal or complete abrogation of the inhibitory effects of alginate on human neutrophil random migration, chemotaxis, and hexose monophosphate shunt activity and lymphocyte transformation were observed following most of these treatments. Physicochemical analysis of degraded MEP revealed a positive correlation between changes in molecular size and viscosity and loss of biological properties. The biological properties of MEP were also shown to be dependent on the structural integrity of the O-acetyl groups substituted for the mannuronic acid residues. The results show that the capacity of MEP to suppress neutrophil and lymphocyte functions is dependent on its acetyl content and the physical properties of large size and viscosity and may provide part of the explanation for the propensity of mucoid P. aeruginosa to persist in the airways of patients with cystic fibrosis. These findings highlight the important role of MEP as one of the virulence factors in the pathogenesis of inflammatory damage and subsequent pulmonary destruction in cystic fibrosis.

Suppression of neutrophil and lymphoproliferative responses in vitro by itraconazole but not fluconazole.

Itraconazole and fluconazole are triazole compounds recently licensed for the therapy of systemic fungal infections. At 10 micrograms/ml concentrations, itraconazole was found to suppress neutrophil chemotaxis, random movement, deoxyglucose uptake and hexose-monophosphate shunt activity to the same extent as ketoconazole, an older generation azole antifungal. Itraconazole was also found to suppress mitogen-induced lymphocyte transformation to the same extent as ketoconazole at concentrations as low as 1 microgram/ml. By contrast, significant inhibition of both neutrophil and lymphocyte functions was not observed with fluconazole at concentrations as high as 50 micrograms/ml. These results suggest that fluconazole may be less immunotoxic than itraconazole, and may be more suitable for use in immunocompromised patients.

In vitro immunosuppressive and anti-phagocytic properties of the exopolysaccharide of mucoid strains of Pseudomonas aeruginosa.

The exopolysaccharide (EPS) of Pseudomonas aeruginosa was found to significantly inhibit neutrophil random movement, chemotaxis and degranulation at concentrations as low as 0.3 microgram/ml. Neutrophil adherence, respiratory burst and bactericidal capacity were inhibited by EPS concentrations of greater than or equal to 3 micrograms/ml. Similarly, mitogen-induced lymphocyte transformation was more sensitive to the inhibitory effects of EPS than natural-killer cell cytotoxicity. These results cannot be explained by simple mechanical blockade, as additions of EPS as late as 48 h after the initiation of lymphocyte cultures still resulted in a significant inhibition of lymphocyte transformation. However, the inhibitory effects of EPS can be reversed by extensive washing of treated lymphocytes. These results suggest that the propensity of mucoid P. aeruginosa to persist in cystic fibrosis may be explained in part by the ability of EPS to interfere with host immunity.

Direct activation of human polymorphonuclear leukocytes by Pseudomonas aeruginosa.

Brief exposure of polymorphonuclear leukocytes (PMNs) to unopsonized Pseudomonas aeruginosa resulted in significant enhancement of PMN adherence and 3H-deoxyglucose uptake, two important indicators of PMN activation. Dose-response and time-course experiments show that maximal stimulation of PMNs occurred at a PMN: bacteria ratio of 10:1 and exposure time of 10 min. The PMN-stimulatory capacity of P. aeruginosa was completely or partially abolished by treatment with formalin, heat, ultrasonication and ultraviolet (UV) irradiation, all of which affect the integrity of ligands on the bacteria surface. The putative glycoprotein ligand(s) contains galactose rather than glucose as shown by the ability of galactose in the medium to abrogate PMN-stimulatory activity. This PMN-stimulatory activity was not mediated by soluble factor(s) released from either P. aeruginosa or PMNs as shown by experiments with appropriate supernatants. Finally, PMN-stimulating activity was also observed with P. maltophilia and P. pseudomallei, but not by the other Pseudomonas spp. such as P. cepacia and P. fluorescens. These results suggest that P. aeruginosa and other Pseudomonas spp. may have little capacity to circumvent PMN host defences. This may account in part for their limited pathogenic role as opportunistic micro-organisms, for the severe inflammatory lesions seen in Pseudomonas infections when they do occur, and is consistent with the fact that infection with these organisms is commonly associated with impaired quantity or function of PMNs.