Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Salivary concentrations of IL-8 and IL-1ra after HIIT and MICT in young, healthy adults: A randomized exercise study.

The purpose of this study was to determine whether six weeks of high intensity interval training (HIIT) would lead to greater changes in resting concentrations of salivary IL-8 and IL-1ra than moderate intensity continuous training (MICT) in young, healthy adults, and to determine whether changes in IL-8 and IL-1ra after six weeks of either HIIT or MICT were associated with changes in maximal exercise capacity (VO2max). Participants were randomly assigned to 6 weeks of HIIT (n = 12) or MICT (n = 11), matched for workload. Saliva samples were collected at the beginning (T1) and end (T2) of the intervention, and analyzed for IL-8 and IL-1ra. Participants in both groups had significant improvements in VO2max; there were no group differences in improvements. A greater reduction in IL-8 was observed in the MICT group when compared to the HIIT group (HIIT median: -9.5; MICT median: -82.3 pg/µg of protein; U = 11.5, p < 0.001). When combining the HIIT and MICT group, there were significant reductions in IL-8 from T1 to T2. There was no correlation between changes in IL-8 (r < 0.00) or IL-1ra (r = -0.013) with changes in VO2max. In conclusion, 6 weeks of exercise training leads to a reduction in IL-8; MICT may lead to greater reductions when compared to HIIT. Future research examining longer intervention periods is needed to further elucidate the effects of HIIT and MICT on different pro and anti-inflammatory cytokines.

Direct and indirect predictors of burden among Bedouin caregivers of family members with terminal cancer in Israel.

Objective: The diverse demands of cancer care, which require time, psychological, physical, and material resources, often lead to caregiver burden. Studies with caregivers from ethnic minority groups suggest that they have unique beliefs and may experience different perceptions of role demands and caregiving. The aim of this study was to identify direct and indirect predictors of burden among Bedouin caregivers of family members with terminal cancer in Israel.Methods: A total of 101 Bedouin family caregivers of terminal cancer patients participated in this study. Participants were recruited from the oncology department of the largest medical center in southern Israel. The questionnaire battery included the Arabic version of the Zarit Burden Interview and other reliable measures validated for cancer caregiving. We performed path analyses on data allowing us to identify hypothesized, and un-hypothesized predictors of burden in this understudied population.Results: Most caregivers were adult children, followed by spouses, siblings and other family members. In our model, caregiver burden was directly predicted by depressive symptoms and (absence of) social support. Burden was indirectly predicted by quality of life (via depressive symptoms), optimism (via social support), emotional exhaustion (via quality of life and depressive symptoms) and mortality communication (via emotional exhaustion, quality of life and depressive symptoms).Conclusion: Social support and depression are the most important factors among all studied measures. Culturally-tailored intervention programs are required to foster community care and mitigate burden for Bedouin and other ethnic minority groups in Israel.

SYSTEMS-2: A randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma.

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20 Gy/5#) or dose escalated treatment (36 Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM.

Expert opinion on advanced techniques for hemostasis in liver surgery.

BACKGROUND: Reduction of perioperative blood loss and intraoperative transfusion are two major factors associated with improving outcomes in liver surgery. There is currently no consensus as to the best technique to achieve this. METHODS: An international Panel of Experts (EP), made up of hepatobiliary surgeons from well-known high-volume centres was assembled to share their experience with regard to the management of blood loss during liver resection surgery. The process included: a review of the current literature by the panel, a face-to-face meeting and an on-line survey completed by the EP prior to and following the face-to-face meeting, based on predetermined case scenarios. During the meeting the most frequently researched surgical techniques were appraised by the EP in terms of intraoperative blood loss. RESULTS: All EP members agreed that high quality research on the subject was lacking. Following an agreed risk stratification algorithm, the EP concurred with the existing research that a haemostatic device should always be used along with any user preferred surgical instrumentation in both open and laparoscopic liver resection procedures, independently from stratification of bleeding risk. The combined use of Ultrasonic Dissector (UD) and saline-coupled bipolar sealing device (Aquamantys(®)) was the EP preferred technique for both open and laparoscopic surgery. CONCLUSIONS: This EP propose the use of a bipolar sealer and UD for the best resection technique and essential equipment to minimise blood loss during liver surgery, stratified according to transfusion risk, in both open and laparoscopic liver resection.

SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.

BACKGROUND: Cure of lung cancer is impossible without local tumour control. This can be compromised by accelerated repopulation of tumour cells during radiotherapy and chemotherapy. A strategy to minimise accelerated repopulation might improve local control. We investigated whether concurrent chemo-radiotherapy could be given safely over four weeks. METHODS: We conducted a randomised phase II trial in which patients with inoperable Stage III Non-Small Cell Lung Cancer (NSCLC) received a radical radiation dose over four weeks rather than conventional fractionation. Treatment was given either sequentially or concurrently with three to four cycles of cisplatinum and vinorelbine. 130 patients with inoperable stage III NSCLC and PS 0-1 were randomised to receive cisplatinum and vinorelbine with either sequential or concurrent chemo-radiation using 55Gy in 20 fractions over four weeks. The primary end-point was treatment related mortality. Secondary end-points were toxicity and survival. FINDINGS: Treatment related mortality was: 2.9% (exact 95% confidence interval [CI] 0.36-10.2%) and 1.7% (exact 95% CI 0.043-9.1%) for the Concurrent and Sequential group respectively; relative risk (RR) 1.25; (95% CI 0.55, 2.84). Toxicity was similar between arms; grade 3 or worse oesophagitis was 8.8% versus 8.5%; RR 1.02 (95% CI 0.58, 1.79). OS HR was 0.92; 95% CI (0.60-1.39; p=0.682). The 2 year overall survival rates were: 50% versus 46%; RR 1.06 (95% CI 0.77, 1.46) for Concurrent versus Sequential. INTERPRETATION: A strategy to minimise the effects of accelerated repopulation using accelerated hypofractionated radiotherapy with chemotherapy is feasible, and reasonably safe for patients with stage III NSCLC. The reported two year survival is promising and suggests that a four week regime of radiotherapy should be compared with conventionally fractionated radiotherapy in an adequately powered randomised controlled phase III trial.

Radiotherapy for the treatment of pain in malignant pleural mesothelioma: a systematic review.

Radiotherapy is commonly used to treat pain in malignant pleural mesothelioma (MPM). The purpose of this systematic review is to examine the evidence for this practice. Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases were searched. Eligible studies met the following criteria: MPM (histological or radiological diagnosis), radiotherapy given with the intent of improving pain, response rates to radiotherapy reported, dose and fractionation reported and the relationship between radiotherapy and pain response explored. All studies had independent review and were graded according to evidence level. Eight studies met the eligibility criteria. Two studies were prospective single arm phase II studies while the remainder were retrospective case series. All were graded as either Level 2 or Level 3 evidence. Due to marked heterogeneity among studies, quantitative synthesis of results was not possible. No high quality evidence currently exists to support radiotherapy in treating pain in MPM. Studies focusing on clear pain endpoints and improving target delineation are needed. Such studies should also use modern radiotherapy techniques and concentrate on dose escalation.

Further confirmation of the psychometric properties of responses to the psychological medicine inventory -student version.

CONTEXT: The Psychological Medicine Inventory (PMI) was first developed to measure physicians' reported interest level, confidence and perceived ability to address the psychological aspects of patient care. A student version of this scale has since been proposed (PMI-S). OBJECTIVE: To further examine the psychometric properties of responses to this student version and to confirm a 2-factor response structure. METHODS: A total of 213 first-year medical students at Ben-Gurion University of the Negev participated in this study. They completed the PMI-S (translated into Hebrew) and a socio-demographic questionnaire. The viability of the 2-factor structure of PMI-S responses was assessed using confirmatory factor analysis (CFA). FINDINGS: Consistent with the original English language version, CFA supported a 2-factor solution (i.e., psychological abilities and psychological sensitivity). All goodness-of-fit indices were found to be within ideal parameters. DISCUSSION AND CONCLUSIONS: Results of this study suggest that the PMI-S can be used to assess psychosocial competence and abilities of medical students and to evaluate the effectiveness of psycho-educational programs aimed at improving their psychosocial abilities.

Is concurrent chemoradiation the standard of care for locally advanced non-small cell lung cancer? A review of guidelines and evidence.

In the past 15 years, the treatment of locally advanced non-small cell lung cancer (NSCLC) has shifted from radiotherapy alone. There are now schedules using induction chemotherapy, concurrent chemoradiation using either radiosensitising doses of chemotherapy or full-dose chemotherapy, consolidation chemotherapy after radiation or combinations of these options. There is no consensus on the optimal chemotherapy regimen and its scheduling and the issue of radiation dose and optimal fractionation equally remains unresolved. This overview is in two sections. First, we have evaluated a selection of international guidelines on the management of locally advanced NSCLC. We assessed the methodology by which individual guidelines were produced and the levels of evidence quoted in support of the recommendations. Second, we have updated the literature search of the 2004 Cochrane review on concurrent chemoradiation. Trials were identified that compared sequential with concurrent chemoradiation using median survival as the primary outcome measure. Two-year survival and toxicity were evaluated as secondary outcome measures. Eleven trials were identified, of which six fulfilled criteria for inclusion. The median survival for concurrent treatment was 16-17 months compared with 13-15 months with sequential treatment. Treatment-related mortality was 3% for concurrent treatment and 1.7% for sequential treatment. The rate of grade 3 or worse oesophagitis was 19% in concurrent treatment compared with 3% for sequential treatment. In conclusion, chemotherapy adds benefit to radiotherapy treatment of locally advanced NSCLC. Concurrent chemoradiation is associated with significant toxicity. The evidence to support concurrent chemoradiation as the standard of care is not robust, in spite of its recommendation within a number of guidelines. Further trials should be supported.

Laparoscopic distal pancreatectomy: the Brisbane experience of forty-six cases.

BACKGROUND AND AIMS: Laparoscopic distal pancreatectomy (LDP) is a safe alternative to conventional open distal pancreatectomy, with advantages that include smaller incisions, less pain, and shorter postoperative recovery. Despite these apparent advantages, however, uptake of the procedure has been slow, with only a handful of series published. MATERIAL AND METHODS: All LDPs performed in Brisbane, Australia, over a 10-year period (May 1996 to June 2006) were retrospectively reviewed. RESULTS: Forty-six consecutive LDPs were performed. A variety of lesions were resected, including nine cancers. Twelve patients were converted for oncological (6) or technical reasons (6). The spleen was retained in 14/29 patients, either by main splenic vessel preservation (9) or solely supported by the short gastric vessels (5), resulting in inferior pole infarction in 2 patients. Overall morbidity was 39%, including 15% pancreatic fistula. All fistulas resolved after a median of 6 weeks without re-operation. A non-significant trend toward fewer fistulas with stapled rather than sutured stump closure was observed (13% vs 19%; p=0.43). Median operative duration and hospital stay were 157 min and 7 days, respectively. There was no mortality. CONCLUSION: LDP is a safe alternative to conventional resection for a wide range of lesions. As with open resection, pancreatic fistula is the dominant morbidity, but is generally indolent. While spleen preservation is often possible, care must be taken to avoid infarction of the inferior pole if the Warshaw technique is utilized.

Low-dose palliative splenic irradiation in haematolymphoid malignancy.

Patients are treated with palliative splenic irradiation (SI) to relieve pain, volume effects and the clinical consequences of hypersplenism. The case records of 19 patients treated with palliative SI at our centre, from April 2003 to November 2004, were reviewed. Twenty-two courses of SI were identified. The radiation doses delivered ranged from 150 to 800 cGy (median 450 cGy). The fraction sizes ranged from 25 to 100 cGy. Parallel-opposed anteroposterior-posteroanterior portals were the most common field arrangement. The target volume was reduced in 18 out of 22 courses. The percentage of field reduction ranged from 0 to 59.57% (mean 24.82%). Twelve of 14 courses were successful in achieving symptom palliation. Of the six patients who received SI for a combination of splenic symptoms and abnormal blood tests, five had symptomatic palliation but only one patient responded haematologically. Of two patients who were started on palliative SI for abnormal haematology alone, only one responded. In summary, 17 of 20 (85%) courses of SI initiated for symptom control resulted in effective palliation. Only two of eight (25%) courses of SI started for abnormal blood counts produced a desired response. To conclude, SI offers an effective and well-tolerated palliative treatment option.

Reliability generalization of responses by care providers to the Zarit Burden Interview.

The Zarit Burden Interview (ZBI) is believed to be the most commonly used measure of caregiver burden. Originally developed more than 20 years ago for use with informal caregivers of community dwelling persons with Alzheimer disease, it has subsequently been administered to a diverse range of patient populations, formal or paid caregivers, and translated into numerous languages. Given that the ZBI is now used more broadly than it was initially intended and first validated, the current study applies the reliability generalization meta-analytic procedure to examine the psychometric properties of responses to the ZBI across populations. Multiple regression with categorical variables was performed to identify factors associated with error variance in ZBI reliability estimates (N=138 data points). Number of items, residence of the care recipient (community) and the Hebrew version each contributed significantly to prediction of internal consistency. These differences, however, were found to be relatively small and within accepted parameters. Generally, responses to the ZBI appear reliable across populations of caregivers and patients. Only versions of the ZBI with more or less than 22-items (nonstandard formats) reflect both statistical and meaningful differences in reliability. Where feasible, it is recommended that the 22-item version of the ZBI be used in future research and clinical practice.

Functions of reminiscence and mental health in later life.

This study examines the extent to which various forms of reminiscence predict life satisfaction and psychiatric distress with and without control for the contribution of personality traits (n=420). Among older adults, reminiscences to revive old problems and to fill a void of stimulation were associated with lower life satisfaction and greater psychiatric distress. Reminiscence to maintain connection with a departed person also predicted psychiatric distress. In contrast, reminiscences for death preparation and to foster conversation were linked with higher life satisfaction. Based on our proposed model of the functions of reminiscence, discussion focuses on adaptive and non-adaptive uses of reminiscence in later life.

Concurrent chemoradiotherapy in non-small cell lung cancer.

BACKGROUND: In a previous meta-analysis of adjuvant chemotherapy in NSCLC there was a 13% reduction in the risk of death in patients receiving radical radiotherapy. This overview specifically excluded trials in which chemotherapy and radiotherapy were given concurrently (NSCLCCG 1995). The use of concurrent chemotherapy and radiotherapy might be seen as a way of increasing the effectiveness of radiotherapy at the same time as reducing the risks of metastatic disease by using chemotherapy. OBJECTIVES: To determine the effectiveness of concurrent chemoradiotherapy as compared to radiotherapy alone with regard to local control and overall survival; and to determine whether the addition of concurrent chemotherapy results in an altered risk of treatment-related morbidity. To compare concurrent with sequential chemoradiotherapy. SEARCH STRATEGY: Electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE with identification of further studies from references cited in the initial identified studies. SELECTION CRITERIA: Randomised trials of patients with stage I-III non-small cell lung cancer (NSCLC) undergoing radical radiotherapy and randomised to receive concurrent chemoradiotherapy versus radiotherapy alone, or concurrent versus sequential chemoradiotherapy. DATA COLLECTION AND ANALYSIS: Identified trials were reviewed independently by both reviewers. Relative risks (calculated according to a random-effects model) were determined with respect to overall survival, progression-free survival and treatment morbidity. MAIN RESULTS: Fourteen randomised studies (including 2393 patients) of concurrent chemoradiotherapy versus radiotherapy alone met the inclusion criteria. In a meta-analysis there was a reduction in risk of death at two years (relative risk (RR) 0.93; 95% CI 0.88 to 0.98; P = 0.01). Similar improvements in two-year locoregional progression-free survival (RR 0.84; 95% CI 0.72 to 0.98; P = 0.03) and progression-free survival at any site (RR 0.90; 95% CI 0.84 to 0.97; P = 0.005) were also seen in those receiving concurrent chemoradiotherapy. Subgroup analysis suggested the possibility of a greater benefit from regimens which incorporated once daily fractionation of radiotherapy or a higher total chemotherapy dose. The incidence of acute oesophagitis, neutropenia and anaemia were significantly increased by concurrent chemoradiotherapy. In a meta-analysis of three trials of concurrent versus sequential chemoradiotherapy there was a significant reduction in the risk of death at two years with concurrent treatment (RR 0.86; 95% CI 0.78 to 0.95; P = 0.003) but potentially at the expense of toxicity, although data was incomplete. REVIEWERS' CONCLUSIONS: With concurrent chemoradiotherapy there was a 14% reduction in risk of death at two years compared to sequential chemoradiotherapy, and a 7% reduction compared to radiotherapy alone. In both cases there was some increase in acute oesophagitis. Caution is advised in adopting concurrent chemoradiotherapy as the standard of care because of uncertainties about the true magnitude of benefit in comparison with sequential chemoradiotherapy. With short follow up and uncertainties about toxicity in the identified studies, the optimal chemotherapy regimen remains uncertain. The confounding effects of treatment-related anaemia and gaps in treatment due to toxicity require further investigation.

Bilateral spontaneous vertebral artery dissection: management during labor and vaginal delivery.

We report the successful management of labor and delivery of a parturient with a history of spontaneous bilateral vertebral artery dissection. We also outline the reasons why the obstetric anesthetist should be aware of this condition as well as other cranio-cervical dissections.

The poor quality of information about laparoscopy on the World Wide Web as indexed by popular search engines.

BACKGROUND: This study was undertaken to determine the quality of information on the Internet regarding laparoscopy. METHODS: Four popular World Wide Web search engines were used with the key word "laparoscopy." Advertisements, patient- or physician-directed information, and controversial material were noted. RESULTS: A total of 14,030 Web pages were found, but only 104 were unique Web sites. The majority of the sites were duplicate pages, subpages within a main Web page, or dead links. Twenty-eight of the 104 pages had a medical product for sale, 26 were patient-directed, 23 were written by a physician or group of physicians, and six represented corporations. The remaining 21 were "miscellaneous." The 46 pages containing educational material were critically reviewed. At least one of the senior authors found that 32 of the pages contained controversial or misleading statements. All of the three senior authors (LKN, NAO, GAF) independently agreed that 17 of the 46 pages contained controversial information. CONCLUSION: The World Wide Web is not a reliable source for patient or physician information about laparoscopy. Authenticating medical information on the World Wide Web is a difficult task, and no government or surgical society has taken the lead in regulating what is presented as fact on the World Wide Web.