Practice patterns in management of differentiated thyroid cancer since the 2014 British Thyroid Association (BTA) guidelines.

BACKGROUND: The updated 2014 BTA guidelines emphasised a more conservative, risk adapted model for the management of low-risk differentiated thyroid cancer (DTC). In comparison to historical approach of total thyroidectomy combined with radioactive iodine, treatment de-escalation is increasingly supported. AIMS: To evaluate the impact of the updated BTA guidelines on the management of DTC cases at regional UK centre. METHODS: All DTC patients were retrospectively identified from regional thyroid MDT database between Jan2009-Dec2020. Oncological treatment and clinico-pathological characteristics were analysed. RESULTS: 623 DTC cases were identified; 312 (247 female: 65 male) between 2009 and 2014 and 311 (225 female: 86 male) between 2015 and 2020. Median age is 48 years (range 16-85). By comparing pre- and post-2015 cohorts, there was a significant drop in total thyroidectomy (87.1% vs 76.8%, p = 0.001) and the use of radioactive iodine (RAI) (73.1% vs 62.1%, p = 0.003) in our post-2015 cohort. When histological adverse features were analysed, extra-thyroidal extension (4.2% vs 17.0%, p=< 0.001), lymphovascular invasion (31.4% vs 50.5%, p=<0.001) and multi-centricity (26.9% vs 43.4%, p = 0.001) were significantly increased in the post 2015 cohort. Nonetheless, total thyroidectomy (TT) remains the treatment choice for low risk T1/2 N0 M0 disease in 65.3% (124/190) in post-2015 cohort for several reasons. Reasons include adverse histological features (50.8%), benign indications (32.5%), contralateral nodules (11.7%), patient preference (2.5%), and diagnostic uncertainty (2.5%). CONCLUSION: Our study confirms a move towards a more conservative approach to patients with low-risk DTC in the UK, which is in keeping with the BTA 2014 guideline and international trends, but total thyroidectomy remains prevalent for low risk T1/2 N0 M0 disease for other reasons.

Oncological outcomes in differentiated thyroid cancer in South East Scotland.

BACKGROUND: Differentiated thyroid cancer (DTC) is increasing in incidence but little is known about oncological outcomes for patients treated in the UK. Internationally there is a move toward conservative treatment of DTC. However, this is based on evidence from outside the UK. The aim of this study was to analyse oncological outcomes for a contemporary cohort of patients treated in a UK centre. METHODS: Review of 470 consecutive prospectively recorded cases of DTC from the South East of Scotland endocrine MDT 2009-2018. Data on patient, tumour and treatment details as well as recurrence and survival details were extracted from the electronic patient record. RESULTS: Of 470 patients female:male ratio was 3.4:1, median age at presentation was 48 years (range 16-86 years). Overall 193 (41%), 134 (29%), 119 (25%) and 22 (5%) patients were p T1, T2, T3, and p T4 respectively. 385 patients (82%) were pN0, 31 patients (7%) were pN1a and 53 patients (11%) were pN1b. 19 patients (4%) were M1. Of 470 patients 350 (74%) had papillary thyroid carcinoma, 120 patients (26%) had follicular carcinoma. Surgical management was lobectomy, isthumusectomy, total thyroidectomy and lobectomy then completion thyroidectomy in 14%,1%, 41% and 43% cases respectively. 64% patients received radioactive Iodine (RAI) therapy. With a median follow-up of 70 months (range 4-124 months), 5 years overall survival and disease specific survival were 96.7% and 98.5% respectively. The 5 year local recurrence free survival (LRFS), regional recurrence free survival (RRFS), locoregional recurrence free survival (LRRFS), distant recurrence free survival (DRFS) and any recurrence free survivals were 100%, 95.8%, 95.8%, 98.3% and 95% respectively. CONCLUSION: Oncological outcomes for patients treated with DTC were excellent, in keeping with experience from international groups, suggesting that a move towards conservative treatment in the UK seems reasonable.

Clinicopathological features of Differentiated Thyroid Cancer presenting in the UK versus internationally: An observational cohort study.

INTRODUCTION: Very little data are available regarding differentiated thyroid cancer (DTC) managed in the UK, and no UK patients are included in the evidence base upon which international guidelines are based. Therefore, the aim of this study was to compare the clinicopathological features of patients with DTC presenting in a UK population with international patient cohorts. PATIENTS AND METHODS: Data were collected from a prospectively held multi-disciplinary team records from January 2009 to December 2016. The local cohort was compared with cohorts from across the world based on clinicopathological features. Ethical approval was obtained by Lothian Caldicott Guardian (Ref 16 133). RESULTS: 444 cases were diagnosed locally with a median age of 48 years (range 16-86 years). 78% of patients were female. 25% of our patients had follicular carcinoma with an overall N1 rate of 20%. Distant disease was recorded in 5% cases. In comparison with international data, our local cohort had a higher rate of follicular thyroid carcinoma. Variation was seen in terms of age, gender distribution, primary tumour size, nodal and distant disease. In Korea, where thyroid cancer screening has been undertaken, smaller tumours, higher rates of nodal disease and lower rates of distant disease are described. CONCLUSION: In our centre, a higher rate of males is treated with larger primary disease and a higher percentage of follicular carcinoma. The reasons for this geographic variation in clinicopathological features in the UK are unclear. As a result, caution should be applied in translating the international move towards a more conservative approach to DTC in the UK in comparison with other areas of the world.

Combined massive allograft and intramedullary vascularized fibula transfer: the Capanna technique for treatment of congenital pseudarthrosis of the tibia.

Background and purpose - Congenital pseudarthrosis of the tibia (CPT) is caused by local periosteal disease that can lead to bowing, fracturing, and pseudarthrosis. Current most successful treatment methods are segmental bone transport and vascularized and non-vascularized bone grafting. These methods are commonly hampered by discomfort, reoperations, and long-term complications. We report a combination of a vascularized fibula graft and large bone segment allograft, to improve patient comfort with similar outcomes.Patients and methods - 7 limbs that were operated on in 6 patients between November 2007 and July 2018 with resection of the CPT and reconstruction with a vascularized fibula graft in combination with a bone allograft were retrospectively studied. The mean follow-up time was 5.4 years (0.9-9.6). Postoperative endpoints: time to discharge, time to unrestricted weight bearing, complications within 30 days, consolidation, number of fractures, and secondary deformities.Results - The average time to unrestricted weight bearing with removable orthosis was 3.5 months (1.2-7.8). All proximal anastomoses consolidated within 10 months (2-10). 4 of the 7 grafts fractured at the distal anastomosis between 6 and 14 months postoperatively. After reoperation, consolidation of the distal anastomosis was seen after 2.8 months (2-4). 1 patient required a below-knee amputation.Interpretation - This case series showed favorable results of the treatment of CPT through a combination of a vascularized fibula graft and large bone segment allograft, avoiding the higher reintervention rate and discomfort with ring frame bone transport, and the prolonged non-weight bearing with vascularized fibula transfer without reinforcement with a massive large bone segment allograft.

PCR Characterization of Microbiota on Contracted and Non-Contracted Breast Capsules.

BACKGROUND: The aetiology of capsular contracture around breast implants remains unclear. The leading theory is that a subclinical infection around the implant plays a role in the development of capsular contractions. Several studies found associations between the presence of bacteria and the occurrence of capsular contraction. However, it is unclear whether detected bacteria originate from the breast capsule, breast glandular tissue or skin contamination. Moreover, this has never been investigated with molecular techniques. The aim of this study was to assess the bacterial microbiota on breast capsules, glandular tissue and skin using a highly sensitive PCR assay. MATERIALS AND METHODS: Fifty breast capsules were collected during implant removal or replacement. Ten specimens of glandular breast tissue and breast skin were collected in females who were undergoing reduction mammoplasty. A sample specimen (4 mm) was sterilely obtained from all tissues. All specimens were analysed by IS-pro, a 16S-23S interspace region-based PCR assay. RESULTS: Low numbers of Staphylococcus spp. (four species in four capsules) were found on breast capsules. There was no difference in bacterial presence between normal and contracted capsules. The skin of the breast-harboured Streptococcus spp. and Staphylococcus spp. while the glandular tissue was sterile. CONCLUSION: The low numbers of bacteria found on the capsules are most likely caused by contamination during capsule removal. More and larger studies are needed to investigate the bacterial presence on breast capsules using a PCR assay. This is the first study in which breast capsules have been studied using a highly sensitive PCR assay. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Intraoperative evaluation of perfusion in free flap surgery: A systematic review and meta-analysis.

BACKGROUND: Free flap survival relies on adequate tissue perfusion. We aim to give an overview of the available literature of all objective methods to intraoperatively assess free flap tissue perfusion, and the effects on (partial) flap loss. METHODS: A systematic review and meta-analysis according to the PRISMA guidelines was performed (PubMed, Cochrane Library, Embase) regarding English language articles. Meta-analyses were performed by pooling means and slopes using random-effect models. RESULTS: Sixty-four articles were included reporting on 2369 procedures in 2009 patients with various indications. Reported methods were fluorescence imaging (FI), laser Doppler, oxygen saturation, ultrasound, (dynamic) infrared thermography, venous pressure, and microdialysis. Intraoperative tissue perfusion was adequately measured by the use of FI and laser Doppler, leading to surgical intervention or altered flap design, and increased flap survival. Meta-analysis showed a mean time until onset of the dye to become visible of 18.4 (7.27; 29.46, Q P < 0.001) sec. The relative intensity of the flap compared to the intensity curve of normal tissue was 75.92% (65.85; 85.98, Q P = 0.719). The mean difference in the slope value of the oxygen tensions before and after the anastomosis was -0.09 (-0.12; -0;06 Q P = 0.982). No convincing evidence was found for the use of other methods. CONCLUSIONS: Based on the current literature, FI and laser Doppler are most suitable to intraoperatively measure free flap tissue perfusion, resulting in improved flap survival. However, this review was limited by the available literature. Additional studies are necessary to investigate the predictive value of intraoperative perfusion measurement.

Haemorrhage following transoral robotic surgery.

BACKGROUND: To report our experience of postoperative haemorrhage in patients following transoral robotic surgery (TORS). METHODS: Data were collected on patients having TORS. Postoperative haemorrhage within 30 days was graded using the Mayo Clinic grading system. RESULTS: Transoral robotic surgery operations were performed on 122 patients. There were 23 bleeding events classified as minor to severe following 19 operations (16%). Haemorrhage requiring a return to the operating room occurred after 7 operations (6%). The odds of an emergent haemorrhage were 5.19 times greater in patients who had a staged neck dissection after TORS (P = .05). The odds of a postoperative bleeding event were 2.6 times greater in patients receiving a larger resection (P = .107). There were no haemorrhage events in the 36 patients who received a synchronous neck dissection with transcervical ligation of the external carotid artery. CONCLUSIONS: Surgical intervention for TORS haemorrhage occurred in 6% patients. No haemorrhage occurred in patients who had ligation of the external carotid artery.

Two-stage implant-based breast reconstruction compared with immediate one-stage implant-based breast reconstruction augmented with an acellular dermal matrix: an open-label, phase 4, multicentre, randomised, controlled trial.

BACKGROUND: The evidence justifying the use of acellular dermal matrices (ADMs) in implant-based breast reconstruction (IBBR) is limited. We did a prospective randomised trial to compare the safety of IBBR with an ADM immediately after mastectomy with that of two-stage IBBR. METHODS: We did an open-label, randomised, controlled trial in eight hospitals in the Netherlands. Eligible women were older than 18 years with breast carcinoma or a gene mutation linked with breast cancer who intended to undergo skin-sparing mastectomy and immediate IBBR. Randomisation was done electronically, stratified per centre and in blocks of ten to achieve roughly balanced groups. Women were assigned to undergo one-stage IBBR with ADM (Strattice, LifeCell, Branchburg, NJ, USA) or two-stage IBBR. The primary endpoint was quality of life and safety was assessed by the occurrence of adverse outcomes. Analyses were done per protocol with logistic regression and generalised estimating equations. This study is registered at Nederlands Trial Register, number NTR5446. FINDINGS: 142 women were enrolled between April 14, 2013, and May 29, 2015, of whom 59 (91 breasts) in the one-stage IBBR with ADM group and 62 (92 breasts) in the two-stage IBBR group were included in analyses. One-stage IBBR with ADM was associated with significantly higher risk per breast of surgical complications (crude odds ratio 3·81, 95% CI 2·67-5·43, p<0·001), reoperation (3·38, 2·10-5·45, p<0·001), and removal of implant, ADM, or both (8·80, 8·24-9·40, p<0·001) than two-stage IBBR. Severe (grade 3) adverse events occurred in 26 (29%) of 91 breasts in the one-stage IBBR with ADM group and in five (5%) of 92 in the two-stage IBBR group. The frequency of mild to moderate adverse events was similar in the two groups. INTERPRETATION: Immediate one-stage IBBR with ADM was associated with adverse events and should be considered very carefully. Understanding of selection of patients, risk factors, and surgical and postsurgical procedures needs to be improved. FUNDING: Pink Ribbon, Nuts-Ohra, and LifeCell.

Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial.

Background: High-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial. Patients and methods: From August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60-74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years. Results: Patient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%). Conclusion: This subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity. ClinicalTrials.gov Identifier: NCT00078949.

Linkage of clinical trial and administrative data: a survey of cancer patient preferences.

BACKGROUND: Personal health information, including diagnoses and hospital admissions, is routinely collected in administrative databases. Patients enrolling on clinical trials consent to separate collection and storage of their personal health information. We evaluated patient preferences for linking long-term data from administrative databases with clinical trials. METHODS: Adults with cancer attending outpatient clinics at 3 Ontario hospitals were surveyed about their willingness, when faced with the hypothetical scenario of participating in a clinical trial, to provide potentially identifying information such as initials and date of birth to facilitate long-term research access to normally deidentified publicly collected databases. RESULTS: Of 569 patients surveyed, 335 (59%) were women, 452 (79%) were white, 385 (68%) had a post-secondary education, and 386 (68%) had never participated in a clinical trial. Median age in the group was 59 years. Most participants (93%, cohort 1) would allow long-term access to their information and allow personal information to be used to match clinical trial with administrative data. At the time of clinical trial closure, two thirds of participants (68%, cohort 2) preferred to make additional clinical information available through linkage with administrative databases, and 8 (9%) preferred to have no further information made available to researchers. No significant differences were found in the subset of patients who were part of a clinical trial and those who had never participated (p = 0.65). INTERPRETATION: Almost all patients would allow a clinical trial research team to access their confidential information, providing a more comprehensive assessment of an intervention's long-term risks and benefits.

In Sickness and in Health: The Relationships Between Bacteria and Bile in the Human Gut.

Colonization of a human host with a commensal microbiota has a complex interaction in which bacterial communities provide numerous health benefits to the host. An equilibrium between host and microbiota is kept in check with the help of biliary secretions by the host. Bile, composed primarily of bile salts, promotes digestion. It also provides a barrier between host and bacteria. After bile salts are synthesized in the liver, they are stored in the gallbladder to be released after food intake. The set of host-secreted bile salts is modified by the resident bacteria. Because bile salts are toxic to bacteria, an equilibrium of modified bile salts is reached that allows commensal bacteria to survive, yet rebuffs invading pathogens. In addition to direct toxic effects on cells, bile salts maintain homeostasis as signaling molecules, tuning the immune system. To cause disease, gram-negative pathogenic bacteria have shared strategies to survive this harsh environment. Through exclusion of bile, efflux of bile, and repair of bile-induced damage, these pathogens can successfully disrupt and outcompete the microbiota to activate virulence factors.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

A prospective randomised controlled trial of the LMA Supreme vs cuffed tracheal tube as the airway device during percutaneous tracheostomy.

We studied the performance of the LMA Supreme against a cuffed tracheal tube, our standard method of airway control during percutaneous tracheostomy, in 50 consecutive patients from three general critical care units. The primary outcome measure was adequacy of ventilation calculated as the difference in arterial carbon dioxide tension before and after tracheostomy. On an intention-to-treat analysis, there was no difference in the increase in arterial carbon dioxide tension between groups, with a median (IQR [range]) for the LMA Supreme of 0.9 (0.3-1.6 [0-2.8]) kPa, and for the tracheal tube of 0.8 (0.4-1.2 [0-2.5]) kPa, p = 0.82. Eight patients out of 25 (32%) crossed over from the LMA Supreme group to the tracheal tube group before commencement of tracheostomy due to airway or ventilation problems, compared with none out of 25 in the tracheal tube group, p = 0.01, and tracheostomy was postponed in two patients in the LMA Supreme group due to poor oxygenation. There were more clinically important complications in the LMA Supreme group compared with the tracheal tube group.

Synthesis, characterization of poly L(+) lactic acid and its application in sustained release of isosorbide dinitrate.

Poly L(+) lactic acid (PLLA) has become crucial in the biomedical industry for various uses. The direct polycondensation method was used to prepare Poly L(+) Lactic Acid (PLLA). Different catalysts, including metal oxides and metal halides, were used to test the polymerization technique. The effect of the amount of catalysts and the type of coupling agent were investigated. The effect of reaction time and polymerization solvents was also studied. PLLA was loaded with isosorbide dinitrate utilizing the solvent evaporation process. The synthesized polymer-drug system was evaluated by different means such as FT-IR, TGA, DSC, XRD, entrapment efficiency (E.E), drug loading (D.L), particle size analysis, and zeta potential determination. Studies on in-vitro release using UV light at 227 nm at various pH levels were conducted, and the kinetics of release and cytotoxicity using the sulforhodamine B (SRB) assay on human skin fibroblast cells were examined.

Comparative metabolomics reveals how the severity of predation by the invasive insect Cydalima perspectalis modulates the metabolism re-orchestration of native Buxus sempervirens.

The recent biological invasion of box tree moth Cydalima perspectalis on Buxus trees has a major impact on European boxwood stands through severe defoliation. This can hinder further regrowth and threaten survival of populations. In a mesocosm approach and controlled larval density over a 2-month period, responses of B. sempervirens essential and specialized metabolites were characterized using metabolomics, combining 1H-NMR and LC-MS/MS approaches. This is the first metabolome depiction of major Buxus responses to boxwood moth invasion. Under severe predation, remaining green leaves accumulate free amino acids (with the noticeable exception of proline). The leaf trans-4-hydroxystachydrine and stachydrine reached 10-13% and 2-3% (DW), while root content was lower but also modulated by predation level. Larval predation promoted triterpenoid and (steroidal) alkaloid synthesis and diversification, while flavonoids did not seem to have a relevant role in Buxus resistance. Our results reveal the concomitant responses of central and specialized metabolism, in relation to severity of predation. They also confirm the potential of metabolic profiling using 1H-NMR and LC-MS to detect re-orchestration of metabolism of native boxwood after severe herbivorous predation by the invasive box-tree moth, and thus their relevance for plant-insect relationships and ecometabolomics.

Adjunctive hyperbaric oxygen therapy in the management of severe lower limb soft tissue injuries: a systematic review.

PURPOSE: Traumatic crush injuries of the lower limb often accompany severe complications. The incorporation of hyperbaric oxygen therapy to standard trauma care may have the potential to diminish injury-related complications and improve outcome in such cases. This systematic review aims to evaluate the effectiveness of hyperbaric oxygen therapy in the management of severe lower limb soft tissue injuries. METHODS: The electronic databases Medline, Embase and Cochrane Library were searched to identify studies involving patients with crush-associated sever lower limb soft tissue injuries who received hyperbaric oxygen therapy in conjunction with standard trauma care. Relevant data on type of injury, hyperbaric oxygen therapy protocol and outcome related to wound healing were extracted. RESULTS: In total seven studies met the inclusion criteria, involving 229 patients. The studies included two randomized clinical trials, one retrospective cohort study, three case series and one case report. The randomized placebo-controlled clinical trial showed a significant increase in wound healing and decrease in the need for additional surgical interventions in the patient group receiving hyperbaric oxygen therapy when compared to those undergoing sham therapy. The randomized non-placebo-controlled clinical trial revealed that early hyperbaric oxygen therapy reduces tissue necrosis and the likelihood of long-term complications. The retrospective cohort study indicated that hyperbaric oxygen therapy effectively reduces infection rates and the need for additional surgical interventions. The case series and case report presented beneficial results with regard to wound healing when hyperbaric oxygen therapy was added to the treatment regimen. CONCLUSION: Hyperbaric oxygen therapy is generally considered a safe therapeutic intervention and seems to have a beneficial effect on wound healing in severe lower limb soft tissue injuries when implemented as an addition to standard trauma care.

An individual patient-data comparison of combined modality therapy and ABVD alone for patients with limited-stage Hodgkin lymphoma.

BACKGROUND: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. PATIENTS AND METHODS: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. RESULTS: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). CONCLUSIONS: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. CLINICAL TRIALS: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients.

BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.