Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients.

The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

Early lymphocyte collection for anti-CD19 CART production improves T-cell fitness in patients with relapsed/refractory diffuse large B-cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeted to the CD19 B-cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment. METHODS: To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19-CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23). RESULTS: An increased percentage of naïve T cells and increased in vitro T-cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group. CONCLUSION: While improved T-cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression-free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T-cell quality.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

The use of a novel adhesive tissue patch as an aid to anastomotic healing.

Introduction One of the most feared complications of colorectal surgery is anastomotic leak. Numerous techniques have been studied in the hope of decreasing leakage. This study was designed to assess the handling characteristics of a novel adhesive tissue patch (TissuePatch™; Tissuemed, Leeds, UK) applied to colorectal anastomoses in a pilot study. This was with a view to assessing its potential role in aiding anastomotic healing in subsequent trials. Methods A patch was applied to colorectal anastomoses after the surgeon had completed the anastomosis and prior to abdominal closure. Handling characteristics and patient outcomes were recorded prospectively. Results Nine patients were recruited before the study was prematurely terminated. In one patient, the patch fell off and in another patient, the surgeon omitted to apply it. Six patients had significant postoperative problems (1 confirmed leak necessitating return to theatre and excision anastomosis, 3 suspicious of leak on computed tomography delaying discharge, 2 perianastomotic collections). One patient had an uneventful recovery. Conclusions Although the handling characteristics of this novel tissue patch were deemed satisfactory, it appears that wrapping a colorectal anastomosis with an adhesive hydrophilic patch has significant deleterious effects on anastomotic healing. This could be a consequence of the creation of a microenvironment between the patch and the anastomosis that impairs healing. Further research is required to better understand the mechanisms involved. At present, the use of such patches on colorectal anastomoses should be discouraged outside the confines of a well monitored trial.

Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature.

In recent years, anti-CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life-threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B-cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.

A meta-analysis of the effectiveness and safety of kinesiology taping in the management of cancer-related lymphoedema.

Patients with cancer-related lymphoedema (CRL) commonly refuse treatment with bandaging or hosiery because of hot and humid weather conditions. This review aims to determine the effectiveness and safety of kinesiotaping (KT) in the management of CRL compared to compression bandaging or hosiery. A systematic search of the literature was conducted until July 2015. The primary outcomes were reduction in body part volume or circumference and adverse effects of the interventions. The secondary outcomes were subjective experience of the treatment, severity of lymphoedema-related symptoms and patients' quality of life (QoL). Six randomised controlled trials (RCTs) were included in this review. Five were included in the meta-analysis of the primary outcome limb volume (n = 203, KTn = 91, compression n = 112). It revealed no significant difference between the interventions [WMD -205.33 mL CI (-454.69 to 44.04) P = 0.11]. An increased risk of skin complications with KT was reported in five studies affecting between 10% and 21% of patients. Where lymphoedema-related symptoms were reported KT was found to be superior to compression. Paradoxically, patients receiving bandaging reported a higher QoL. KT was not found to be more comfortable than bandaging. KT should only be used with great caution where bandaging cannot be used.

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Preterm birth time trends in Europe: a study of 19 countries.

OBJECTIVE: To investigate time trends in preterm birth in Europe by multiplicity, gestational age, and onset of delivery. DESIGN: Analysis of aggregate data from routine sources. SETTING: Nineteen European countries. POPULATION: Live births in 1996, 2000, 2004, and 2008. METHODS: Annual risk ratios of preterm birth in each country were estimated with year as a continuous variable for all births and by subgroup using log-binomial regression models. MAIN OUTCOME MEASURES: Overall preterm birth rate and rate by multiplicity, gestational age group, and spontaneous versus non-spontaneous (induced or prelabour caesarean section) onset of labour. RESULTS: Preterm birth rates rose in most countries, but the magnitude of these increases varied. Rises in the multiple birth rate as well as in the preterm birth rate for multiple births contributed to increases in the overall preterm birth rate. About half of countries experienced no change or decreases in the rates of singleton preterm birth. Where preterm birth rates rose, increases were no more prominent at 35-36 weeks of gestation than at 32-34 weeks of gestation. Variable trends were observed for spontaneous and non-spontaneous preterm births in the 13 countries with mode of onset data; increases were not solely attributed to non-spontaneous preterm births. CONCLUSIONS: There was a wide variation in preterm birth trends in European countries. Many countries maintained or reduced rates of singleton preterm birth over the past 15 years, challenging a widespread belief that rising rates are the norm. Understanding these cross-country differences could inform strategies for the prevention of preterm birth.

Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients.

PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984-2007.

OBJECTIVE: To assess the public health consequences of the rise in multiple births with respect to congenital anomalies. DESIGN: Descriptive epidemiological analysis of data from population-based congenital anomaly registries. SETTING: Fourteen European countries. POPULATION: A total of 5.4 million births 1984-2007, of which 3% were multiple births. METHODS: Cases of congenital anomaly included live births, fetal deaths from 20 weeks of gestation and terminations of pregnancy for fetal anomaly. MAIN OUTCOME MEASURES: Prevalence rates per 10,000 births and relative risk of congenital anomaly in multiple versus singleton births (1984-2007); proportion prenatally diagnosed, proportion by pregnancy outcome (2000-07). Proportion of pairs where both co-twins were cases. RESULTS: Prevalence of congenital anomalies from multiple births increased from 5.9 (1984-87) to 10.7 per 10,000 births (2004-07). Relative risk of nonchromosomal anomaly in multiple births was 1.35 (95% CI 1.31-1.39), increasing over time, and of chromosomal anomalies was 0.72 (95% CI 0.65-0.80), decreasing over time. In 11.4% of affected twin pairs both babies had congenital anomalies (2000-07). The prenatal diagnosis rate was similar for multiple and singleton pregnancies. Cases from multiple pregnancies were less likely to be terminations of pregnancy for fetal anomaly, odds ratio 0.41 (95% CI 0.35-0.48) and more likely to be stillbirths and neonatal deaths. CONCLUSIONS: The increase in babies who are both from a multiple pregnancy and affected by a congenital anomaly has implications for prenatal and postnatal service provision. The contribution of assisted reproductive technologies to the increase in risk needs further research. The deficit of chromosomal anomalies among multiple births has relevance for prenatal risk counselling.

Nurse-led rapid access vascular examination clinic triage reduces inappropriate referrals for peripheral arterial disease.

INTRODUCTION: Peripheral arterial disease causing intermittent claudication (IC) causes decreased quality of life and significant morbidity. We hypothesized that triage of patients referred with suspected IC at a nurse-led rapid access vascular examination (RAVE) clinic would identify those patients requiring vascular surgery assessment. METHODS: A prospective cohort study was performed. Patients referred with suspected IC were assessed using the Edinburgh claudication questionnaire (ECQ) and arterial Doppler assessment with segmental waveform analysis and calculation of ankle brachial pressure index (ABPI). Data were collected regarding cardiovascular risk and its modification. RESULTS: Of 451 consecutive patients, mean age was 65 years (range 30-89). Cardiovascular risk factors included: 173/451 (38%) current smokers (162/451 (36%) were ex-smokers); diabetes, 22%; hypertension, 46%; ischaemic heart disease (angina), 29%; dyslipidaemia, 27%. Therapeutic risk modifications included: antiplatelet therapy, 64.4%; lipid-lowering therapy, 57.8%. abnormal ABPI readings were present in 264/451 (59%), with ratio <0.9 in 209/451 (46.3%), >1.3 in 48/451 (10.6%), and incompressible vessels 7/451 (1.5%). Normal ABPI (ratio >0.9 and <1.3, triphasic Doppler waveforms) were found in 187/451 (41%), these patient were considered inappropriate referrals. Considering those patient with PAD diagnosed on abnormal ABPI (<0.9 or >1.3), Doppler waveform analysis was more sensitive and specific than ECQ. CONCLUSIONS: Diagnosis of IC with clinical history alone is inaccurate in 41 percent of cases, leading to inappropriate referral to vascular surgery. Doppler waveform analysis had excellent sensitivity and specificity for prediction of ABPI <0.9. ABPI measurement in primary care could result in a more efficient use of clinical resources.

Laparoscopic resection for recurrent Crohn's disease: safety, feasibility and short-term outcomes.

AIM: The safety, feasibility and short-term outcomes of laparoscopic resection were assessed in patients with recurrent ileocolic Crohn's disease. METHOD: A consecutive series of patients was identified from a prospectively collated database. Data included patient demographics, previous medical and surgical treatment, operative details and postoperative course. Data from the original index open operation were collected retrospectively by review of the case notes. RESULTS: Between 2005 and 2009, 27 patients [21 women, mean (range) age 31 years (16-51 years)] underwent laparoscopic resection for recurrent ileocolic Crohn's disease. All had histologically confirmed recurrent disease at the ileocolic anastomosis. Five (18.5%) patients required extended resection for Crohn's colitis, three (11.1%) had fistulating disease and one (3.4%) patient had a psoas abscess. The median (range) operative time was 110 min (70-170 min) with a conversion rate of two (7.4%) of 27 patients. The length of stay was 4 days (2-7 days) with time to return to work or full activity of 3.5 weeks (2-7 weeks). CONCLUSION: Laparoscopic resection of recurrent ileocolic Crohn's disease is safe, feasible and associated with short-term benefits.

In response to: Varadhan KK, Neal KR, Dejong CH, Fearon KC, Ljungqvist O, Lobo DN. The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr 29 (2010) 434-440.

Mulitimodal optimization of perioperative care has widely replaced the traditional management of patients undergoing surgery in the various specialties. Issues relating to compliance to the individual ERAS strategies and the importance of recovery of gut function in the post-operative patient are discussed.

Randomized clinical trial of gut-specific nutrients in critically ill surgical patients.

BACKGROUND: Inadequate gut function is common and may adversely affect prognosis. However, it is difficult to measure and treatment options are limited. This study evaluated whether gut-specific nutrients (GSNs) could stimulate the return of gut function in critically ill patients, and assessed what effect, if any, this would have on patient outcomes. METHODS: Consecutive critically ill patients intolerant to enteral feeding were randomized to receive a cocktail of GSNs or placebo. Administration was for 1 month and patients were followed for 3 months. The primary endpoint was the time to return of normal gut function. RESULTS: Twenty-five patients were randomized to each group. GSN administration was associated with a quicker return of normal gut function (median 164 versus 214 h; P = 0.016), attenuation of the acute-phase response and a lower incidence of sepsis (4 versus 13 patients, P = 0.015) compared with placebo. There were fewer deaths by 3 months in the GSN group but this did not achieve significance (2 versus 7 deaths; P = 0.138). CONCLUSION: GSNs expedite the return of gut function in the critically ill and improve outcomes. Inadequate gut function may be associated with poor prognosis similar to that of other single organ failures. REGISTRATION NUMBER: ISRCTN61157513 (http://www.controlled-trials.com).

Compliance with enhanced recovery programmes in elective colorectal surgery.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are often criticized for being difficult to implement outside clinical trials. This audit evaluated compliance with an ERAS protocol and compared it with that during a trial. METHODS: Compliance was audited by case-note review of 100 consecutive patients undergoing colorectal surgery. This was compared with the compliance in a group of 95 patients who participated in a clinical trial. RESULTS: Fewer patients in the audit group than in the study group received preoperative oral carbohydrate loading (61.0 versus 96 per cent; P < 0.001), a transverse incision (25.0 versus 39 per cent; P = 0.037), early fluid and diet reintroduction (73.0 versus 99 per cent; P < 0.001), and non-opiate postoperative oral analgesia (70.0 versus 99 per cent; P < 0.001). Lower non-opiate oral analgesia use in the audit group was not associated with a commensurate increase in opiate use (P = 0.061). There was no difference between groups in length of hospital stay (median (interquartile range) 7 (5-8) versus 6 (5-7) days respectively), septic morbidity or 30-day mortality rates. CONCLUSION: Observance to some aspects of the ERAS protocol was lower outside the clinical trial. However, this made little difference to patient outcome.

Laparoscopic excision of retrorectal schwannoma.

The short-term benefits of laparoscopic resection for standard tumors of the colon and rectum are well accepted. Retrorectal tumors are relatively uncommon, and there have been few reports of laparoscopic techniques being applied to such tumors. This video article presents a laparoscopic approach to a retrorectal schwannoma, highlights the technical challenges of such a procedure, and offers some operative tips to aid management of such tumors (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A29).