Quality assurance of surgery in the randomized ST03 trial of perioperative chemotherapy in carcinoma of the stomach and gastro-oesophageal junction.

BACKGROUND: The UK Medical Research Council ST03 trial compared perioperative epirubicin, cisplatin and capecitabine (ECX) chemotherapy with or without bevacizumab (B) in gastric and oesophagogastric junctional cancer. No difference in survival was noted between the arms of the trial. The present study reviewed the standards and performance of surgery in the context of the protocol-specified surgical criteria. METHODS: Surgical and pathological clinical report forms were reviewed to determine adherence to the surgical protocols, perioperative morbidity and mortality, and final histopathological stage for all patients treated in the study. RESULTS: Of 1063 patients randomized, 895 (84·2 per cent) underwent resection; surgical details were available for 880 (98·3 per cent). Postoperative assessment data were available for 873 patients; complications occurred in 458 (52·5 per cent) overall, of whom 71 (8·1 per cent) developed complications deemed to be life-threatening by the responsible clinician. The most common complications were respiratory (211 patients, 24·2 per cent). The anastomotic leak rate was 118 of 873 (13·5 per cent) overall; among those who underwent oesophagogastrectomy, the rate was higher in the group receiving ECX-B (23·6 per cent versus 9·9 per cent in the ECX group). Pathological assessment data were available for 845 patients. At least 15 nodes were removed in 82·5 per cent of resections and the median lymph node harvest was 24 (i.q.r. 17-34). Twenty-five or more nodes were removed in 49·0 per cent of patients. Histopathologically, the R1 rate was 24·9 per cent (208 of 834 patients). An R1 resection was more common for proximal tumours. CONCLUSION: In the ST03 trial, the performance of surgery met the protocol-stipulated criteria. Registration number: NCT00450203 ( http://www.clinicaltrials.gov).

Prospects and applications near ferroelectric quantum phase transitions: a key issues review.

The emergence of complex and fascinating states of quantum matter in the neighborhood of zero temperature phase transitions suggests that such quantum phenomena should be studied in a variety of settings. Advanced technologies of the future may be fabricated from materials where the cooperative behavior of charge, spin and current can be manipulated at cryogenic temperatures. The progagating lattice dynamics of displacive ferroelectrics make them appealing for the study of quantum critical phenomena that is characterized by both space- and time-dependent quantities. In this key issues article we aim to provide a self-contained overview of ferroelectrics near quantum phase transitions. Unlike most magnetic cases, the ferroelectric quantum critical point can be tuned experimentally to reside at, above or below its upper critical dimension; this feature allows for detailed interplay between experiment and theory using both scaling and self-consistent field models. Empirically the sensitivity of the ferroelectric T c's to external and to chemical pressure gives practical access to a broad range of temperature behavior over several hundreds of Kelvin. Additional degrees of freedom like charge and spin can be added and characterized systematically. Satellite memories, electrocaloric cooling and low-loss phased-array radar are among possible applications of low-temperature ferroelectrics. We end with open questions for future research that include textured polarization states and unusual forms of superconductivity that remain to be understood theoretically.

Heavy-fermion quantum criticality and destruction of the Kondo effect in a nickel oxypnictide.

A quantum critical point arises at a continuous transformation between distinct phases of matter at zero temperature. Studies in antiferromagnetic heavy-fermion materials have revealed that quantum criticality has several classes, with an unconventional type that involves a critical destruction of the Kondo entanglement. To understand such varieties, it is important to extend the materials basis beyond the usual setting of intermetallic compounds. Here we show that a nickel oxypnictide, CeNiAsO, exhibits a heavy-fermion antiferromagnetic quantum critical point as a function of either pressure or P/As substitution. At the quantum critical point, non-Fermi-liquid behaviour appears, which is accompanied by a divergent effective carrier mass. Across the quantum critical point, the low-temperature Hall coefficient undergoes a rapid sign change, suggesting a sudden jump of the Fermi surface and a destruction of the Kondo effect. Our results imply that the enormous materials basis for the oxypnictides, which has been so crucial in the search for high-temperature superconductivity, will also play a vital role in the effort to establish the universality classes of quantum criticality in strongly correlated electron systems.

Some current problems in perovskite nano-ferroelectrics and multiferroics: kinetically-limited systems of finite lateral size.

We describe some unsolved problems of current interest; these involve quantum critical points in ferroelectrics and problems which are not amenable to the usual density functional theory, nor to classical Landau free energy approaches (they are kinetically limited), nor even to the Landau-Kittel relationship for domain size (they do not satisfy the assumption of infinite lateral diameter) because they are dominated by finite aperiodic boundary conditions.

Presentation and management of gastrointestinal stromal tumours.

Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the gastrointestinal tract. The aim of this study was to present the experience of a single centre. A prospective GIST database from 1997 to 2011 in a tertiary referral centre wa reviewed. 78 patients (36 male/42 female) with a median age of 66 (range 10-93) were diagnosed with GIST during this period. Surgery was the primary treatment for 70 patients (90%); 19 (24%) resections were laparoscopic. Nineteen patients (24%) received Imatinib therapy. At a median follow up of 3 years, 10 patients (15%) had recurrence. Five-year survival was 89%. Surgery remains the mainstay of treatment. Minimally invasive approaches may be carried out with high cure rates. This study highlights the changing presentation and treatment approach, as well as the excellent outcomes achievable for GIST tumours.

Complementary medicine use in patients with head and neck cancer in Ireland.

The objectives of the study were: first, to determine the prevalence of traditional medicine (TM) and complementary and alternative medicine (CAM) use in head and neck cancer patients in Ireland; second, to educate ourselves on the plethora of CAM/TM options available to patients outside the dominion of conventional medicine. The study design consisted of a cross-sectional survey carried out in three head and neck cancer centres. Self-administered questionnaires were distributed to 110 head and neck cancer patients attending the three cancer centres and data were collected for statistical analysis. A total of 106 patients completed the questionnaire; 21.7% of the participants used CAM/TM since their diagnosis with head and neck cancer. CAM/TM usage was higher in female (34.3%) than in male patients (16.2%). CAM/TM use was more common in the 41-50-year age group, in patients with higher educational levels and those holding strong religious beliefs, and also in married than single patients. The most common types of CAM/TM used were spiritual and laying on of hands. The most common reasons reported for using CAM/TM were to counteract the ill effects of treatment and increase the body's ability to fight cancer. Sources of information on CAM/TM were friends (65%), family (48%) and media (21%). This survey reveals a high prevalence of CAM/TM use in head and neck cancer patients, hence emphasising the need for otolaryngologists to educate themselves on the various therapies available to be able to provide informative advice. There is an urgent need for evidence-based investigation of various CAM/TM therapies currently offered to patients.

Superconductivity mediated by polar modes in ferroelectric metals.

The occurrence of superconductivity in doped SrTiO3 at low carrier densities points to the presence of an unusually strong pairing interaction that has eluded understanding for several decades. We report experimental results showing the pressure dependence of the superconducting transition temperature, Tc, near to optimal doping that sheds light on the nature of this interaction. We find that Tc increases dramatically when the energy gap of the ferroelectric critical modes is suppressed, i.e., as the ferroelectric quantum critical point is approached in a way reminiscent to behaviour observed in magnetic counterparts. However, in contrast to the latter, the coupling of the carriers to the critical modes in ferroelectrics is predicted to be small. We present a quantitative model involving the dynamical screening of the Coulomb interaction and show that an enhancement of Tc near to a ferroelectric quantum critical point can arise due to the virtual exchange of longitudinal hybrid-polar-modes, even in the absence of a strong coupling to the transverse critical modes.

Author Correction: Superconductivity mediated by polar modes in ferroelectric metals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Waiting times for access, diagnosis and treatment in a cancer centre.

We analysed the waiting times for patients in a Dublin hospital from 2001 to 2006, and evaluated trends in each of 4 cancer diagnoses; breast, lung, colorectal and upper gastrointestinal (gastric and oesophageal). Measured times were; time from referral to first seen, time from first seen to diagnosis and time from diagnosis to treatment. Patient numbers increased 39% from 529 in 2001 to 737 in 2006. As a result waiting times have increased over the 6 years. While median time from referral to first seen for breast cancer was 7 days, it rose from 2 to 5 days for lung cancer, 1 to 2 days for colorectal cancer, and 1 to 6 days for upper GI cancers. The time from diagnosis to treatment rose from 8 to 15 days (breast), 10 days to 25 (lung), 6 to 14 days (colorectal) and 7 to 13 days (Upper GI). Waiting times however, remain within international standards.

Quality of life and survival in patients treated with radical chemoradiation alone for oesophageal cancer.

AIMS: To report cancer-specific and health-related quality-of-life outcomes in patients undergoing radical chemoradiation (CRT) alone for oesophageal cancer. MATERIALS AND METHODS: Between 1998 and 2005, 56 patients with oesophageal cancer received definitive radical CRT, due to local disease extent, poor general health, or patient choice. Data from European Organization for Research and Treatment of Cancer quality-of-life questionnaires QLQ-30 and QLQ-OES24 were collected prospectively. Questionnaires were completed at diagnosis, and at 3, 6 and 12 months after CRT where applicable. RESULTS: The median follow-up was 18 months. The median overall survival was 14 months, with a 51, 26 and 13% 1-, 3- and 5-year survival, respectively. At 12 months after treatment there was a significant improvement compared with before treatment with respect to dysphagia and pain. Global health scores were not significantly affected. CONCLUSIONS: Considering the relatively short long-term survival for this cohort of patients, maximising the quality of those final months should be very carefully borne in mind from the outset. The health-related quality-of-life data reported herein helps to establish benchmarks for larger evaluation within randomised clinical trials.

Health-related quality of life assessment at presentation may predict complications and early relapse in patients with localized cancer of the esophagus.

SUMMARY: Health-related quality of life (HR-QOL) assessment in esophageal cancer is increasingly performed. However, the association of baseline HR-QOL in predicting outcome is unclear. This study aimed to assess the impact of HR-QOL scores at diagnosis with major morbidity, mortality, failure to progress to surgery, recurrence within 1 year, and survival in patients with localized esophageal cancer. The European Organization for Research and Treatment of Cancer's quality of life questionnaire was completed at diagnosis. Univariate and multivariate logistic regression were used to investigate the relationship between baseline HR-QOL and outcomes adjusting for confounding variables. A total of 185 patients with localized esophageal cancer were included, 89 undergoing multimodal therapy and 96 surgery alone. Global QOL scores were significantly associated with in-hospital mortality (P = 0.020) but not with major morbidity (P = 0.709) or 1-year survival (P = 0.247). Symptoms of fatigue and dyspnea at baseline were significantly (P < 0.05) associated with major morbidity, in-hospital mortality, and survival in univariate analysis. After adjusting for known confounding variables in multivariate analysis, only worse dyspnea score remained predictive of in-hospital mortality and a worse fatigue score remained predictive of 1-year survival. HR-QOL was of no benefit in predicting survival in multivariate analysis that identified pathological nodal status as the most significant factor. HR-QOL questionnaires may be helpful in preoperative assessment of risk. It is possible that patients with unrecognized micrometastatic disease at the time of surgery may report worse systemic symptoms at diagnosis, in particular fatigue and dyspnea, and these and global QOL scores may also identify poorer reserves that may increase in-hospital morbidity and mortality postoperatively.

The Rossetti-Nissen fundoplication--effective in managing gastro-oesophageal reflux disease.

BACKGROUND: The report herein details a prospective audit of a unit's eight-year experience of the Rossetti-Nissen fundoplication using a predominantly laparoscopic technique, selective hiatal repair, no bougie and a standardised protocol of pre- and post-operative functional endoscopic and symptom assessment. METHODS: Three hundred and seventy-eight patients underwent the Rossetti-Nissen fundoplication. All patients had documented data on endoscopy, health related quality of life (HR-QoL), surgical details and complications pre-operatively and at six months post-operatively. Repeat physiological testing was performed at six months. RESULTS: At a median follow-up of six (range 3-13) months there was improved symptom scoring and HR-QoL after fundoplication with an 89% patient satisfaction rate. Ninety-five patients (25%) reported some early dysphagia, and 91 of these reported the outcome of surgery to be excellent or good. Thirty-eight patients (10%) had recurrent heartburn and 28 (7%) were back on medication at six months post-operatively. At follow-up pH study at a median of six months, 89% of patients had normalised acid reflux scores. CONCLUSIONS: Rossetti-Nissen fundoplication, with no use of an oesophageal bougie and no division of short gastric vessels, is an effective procedure giving 89% patient satisfaction and significant improvement in QoL parameters and physiological measurements.

Hemithyroidectomy for benign thyroid disease: who needs follow-up for hypothyroidism?

OBJECTIVE: To identify the incidence and possible risk factors for the development of hypothyroidism following hemithyroidectomy and to determine a simple protocol for the post-op monitoring of thyroid function. DESIGN: Prospective study. SETTING: Tertiary Referral Centre. PATIENTS: Eighty-two consecutive patients who underwent hemi-thyroidectomy between May 2003 and May 2005 were included. The clinical and pathological factors were obtained and statistically analysed. RESULTS: Eighteen per cent of patients became hypothyroid post-operatively. Multivariate analysis demonstrated that risk factors for hypothyroidism following hemithyroidectomy included a pre-operative [TSH] >1.6 microIU/L [P = 0.008, hazard ratio (HR) 14, 95% confidence interval (CI) 2-54] and lymphocytic infiltration graded 3+ or more (P < 0.001, HR 42, 95% CI, 8-195%). There was no relationship between age, sex or weight of resected tissue and the risk of hypothyroidism. CONCLUSION: Patients with raised pre-operative [TSH] or with lymphocytic infiltration of their thyroid specimen should undergo regular testing of thyroid function within the first year of surgery. In all other patients, thyroid function at 12 months is sufficient.

Co-enrolment of Participants into Multiple Cancer Trials: Benefits and Challenges.

Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial - a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible - limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research.

Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers.

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.

A multicenter trial of myeloablative clofarabine and busulfan conditioning for relapsed or primary induction failure AML not in remission at the time of allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.

High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose-intense induction as initial therapy for metastatic breast cancer.

We assessed the toxicity and efficacy of high-dose chemotherapy consolidation with reinfusion of purged autologous bone marrow in women with metastatic breast cancer responding to a dose-intense outpatient regimen. Thirty women with hormone-unresponsive metastatic breast cancer, previously untreated with adjuvant doxorubicin or with any chemotherapy for metastatic disease, were treated with cyclophosphamide, methotrexate, doxorubicin, fluorouracil, vincristine, and leucovorin for 16 weeks. Twenty-four patients responded to therapy; 8 showed a complete response, and 16 showed a partial response. These patients proceeded to the next phase of the protocol, ie, marrow harvest and treatment with 6000 mg/m2 cyclophosphamide and 800 mg/m2 thiotepa given over 4 days. Harvested marrow was purged with 100 micrograms/mL 4-hydroperoxycyclophosphamide, and all patients engrafted satisfactorily. The predominant side effects were myelosuppressive and gastrointestinal, and there were no deaths from toxic effects. Three of the 16 patients who showed a partial response after the outpatient phase of treatment achieved a complete response after high-dose therapy. The partial response seen in two more patients converted to a complete response at all sites except bone. The median time to disease progression for all patients in this study was 13 months, and the median survival was 22 months. Four of the original 30 patients remained without disease progression a median of 27 months from entry into the study. This study indicates that this dose-intense regimen can be safely administered, even with the use of purged marrow, with an acceptable toxicity profile. This approach results in a high response rate in women with metastatic breast cancer and could form the basis for a regimen to be tested in the high-risk adjuvant setting.

Uniaxial ferroelectric quantum criticality in multiferroic hexaferrites BaFe12O19 and SrFe12O19.

BaFe12O19 is a popular M-type hexaferrite with a Néel temperature of 720 K and is of enormous commercial value ($3 billion/year). It is an incipient ferroelectric with an expected ferroelectric phase transition extrapolated to lie at 6 K but suppressed due to quantum fluctuations. The theory of quantum criticality for such uniaxial ferroelectrics predicts that the temperature dependence of the electric susceptibility χ diverges as 1/T(3), in contrast to the 1/T(2) dependence found in pseudo-cubic materials such as SrTiO3 or KTaO3. In this paper we present evidence of the susceptibility varying as 1/T(3), i.e. with a critical exponent γ = 3. In general γ = (d + z - 2)/z, where the dynamical exponent for a ferroelectric z = 1 and the dimension is increased by 1 from deff = 3 + z to deff = 4 + z due to the effect of long-range dipole interactions in uniaxial as opposed to multiaxial ferroelectrics. The electric susceptibility of the incipient ferroelectric SrFe12O19, which is slightly further from the quantum phase transition is also found to vary as 1/T(3).

Phase I study of combination drug purging for autologous bone marrow transplantation.

In a phase I clinical trial of autologous bone marrow transplantation, we determined the feasibility of ex vivo purging with high concentrations of pharmacologics in combination. Light-density cells isolated from the grafts of 26 patients with acute leukemia or lymphoblastic lymphoma were treated with 4-hydroperoxycyclophosphamide (4-HC; 30 to 60 micrograms/mL), vincristine (Vcr; 1.5 to 3.0 micrograms/mL), and methylprednisolone sodium succinate (MP; 5 mg/mL). All patients received marrow-lethal induction therapy followed by infusion of the treated grafts. Three patients died of transplant-related complications before achieving peripheral blood recovery of greater than 0.5 x 10(9) granulocytes per liter. All other patients achieved this parameter of engraftment at a median of 35 days after marrow infusion. The median time to last platelet transfusion was 45 days. These durations of aplasia were similar to those experienced by other patients receiving density-gradient separated grafts treated with 60 micrograms/mL of 4-HC as a single agent. No patient required infusion of untreated reserve marrow because of engraftment failure. The colony-forming unit-granulocyte macrophage (CFU-GM) content of the grafts after purging predicted these parameters of engraftment. Colony-forming unit-leukemia (CFU-L) cultured from the grafts of 12 of the patients treated for acute lymphoblastic leukemia (ALL) were considerably more sensitive to the combination regimen than to 4-HC alone; the sensitivity of CFU-GM from these patients did not differ between the two regimens. The results of this trial indicate the feasibility of treating autologous bone marrow grafts with high concentrations of pharmacologics in combination. The use of combinations may increase the efficacy of ex vivo purging without increasing the toxicity to normal hematopoietic cells.

Factors that influence collection and engraftment of autologous peripheral-blood stem cells.

PURPOSE: To analyze factors that affect the collection of peripheral-blood stem cells (PBSC) before transplant and the tempo of engraftment after transplant. PATIENTS AND METHODS: A consecutive series of 243 patients with breast cancer (n = 87), malignant lymphoma (n = 90), multiple myeloma (n = 32), or other malignancies (n = 34) had PBSC collected following stimulation with colony-stimulating factors (CSFs) or after chemotherapy followed by CSF. Infusion of PBSC was performed following myeloablative chemotherapy with chemotherapy with or without total-body irradiation (TBI). Postinfusion CSFs were administered to 72 patients. An analysis of factors that influence CD34+ cell yield was performed by linear regression. Cox regression analysis was used to determine factors that affect the kinetics of granulocyte and platelet recovery following infusion of PBSC. RESULTS: Mobilization with chemotherapy followed by CSF, a diagnosis of breast cancer, absence of marrow disease, no prior history of radiation therapy, and fewer cycles of conventional-dose chemotherapy were associated with a higher average daily yield of CD34+ cells. In the multivariate analysis, the CD34 content of infused cells and the use of a posttransplant CSF influenced neutrophil recovery after infusion of PBSC. CD34 content was also important for predicting platelet recovery. The use of postinfusion CSF was associated with a significant delay in platelet recovery in patients who received less than 5.0 x 10(6) CD34+ cells/kg, but there was no discernable effect in patients who received greater than 5.0 x 10(6) CD34+ cells/kg. CONCLUSION: Disease status and prior treatment influence the ability to mobilize PBSC. CD34 cell dose is an important predictor of engraftment kinetics after PBSC transplant, regardless of disease or mobilization technique. The use of postinfusion CSF improves neutrophil recovery, but at low CD34 doses can delay platelet recovery.