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.

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.

Diverse migratory pathways in the developing cerebral cortex.

During early development of the mammalian cerebral cortex, young neurons migrate outward from the site of their final mitosis in the ventricular zone into the cortical plate, where they form the adult cortex. Time-lapse confocal microscopy was used to observe directly the dynamic behaviors of migrating cells in living slices of developing cortex. The majority of cells migrated along a radial pathway, consistent with the view that cortical neurons migrate along radial glial fibers. A fraction of cells, however, turned within the intermediate zone and migrated orthogonal to the radial fibers. This orthogonal migration may contribute to the tangential dispersion of clonally related cortical neurons.

Dynamic changes in optic fiber terminal arbors lead to retinotopic map formation: an in vivo confocal microscopic study.

Dynamic remodeling of retinal ganglion cell terminal arbors has been proposed to contribute to formation of the topographically ordered retinotectal projection. To test this directly, the growth of individual terminal arbors was observed in live X. laevis tadpoles using a confocal microscope to visualize their complex three-dimensional structure. During initial development, nasal and temporal retinal arbors covered overlapping tectal areas. Despite subsequent remodeling, the dimensions and positions of the temporal arbors remained relatively stable. In contrast, the nasal arbors grew caudally, as they extended caudal branches and retracted rostral branches. These results suggest that differences in the remodeling of the nasal and temporal arbors lead to the emergence of retino-topography along the rostrocaudal axis of the tectum. All the terminal arbors were dynamic, including those with stable dimensions, suggesting that continual remodeling of arbors may be a universal feature of neuronal projections.

Rapid remodeling of retinal arbors in the tectum with and without blockade of synaptic transmission.

Dynamic rearrangements of axon terminal arbors may be critical for establishing appropriate connections in the developing nervous system. Here, the changes in complex retinal axon arbors in the tecta of live Xenopus larvae were followed during the formation of the topographic retinotectal projection. Three-dimensional reconstructions of terminal arbors made with a confocal microscope at hourly intervals revealed rapid remodeling of arbor extensions. Shorter branches were extended and retracted very rapidly, suggesting that they probe the environment for the optimal sites to form stable branches. About 27% of longer branches were present throughout the entire observation period and may be sites of stabilized synaptic contacts. Treatment of the animals to block postsynaptic activity resulted in increased rates of arbor rearrangements, which may coincide with decreased synapse stability. These studies reveal the dynamic behavior of nerve arbors and provide estimates for the lifetimes of retinotectal branches.

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.

Double-blind, placebo-controlled, dose-response trial of oral clodronate in patients with bone metastases.

PURPOSE: Despite evidence that clodronate inhibits tumor-induced osteolysis, no studies have directly assessed the optimal dose for long-term treatment. The aim of this double-blind, placebo-controlled study was to determine the safety and efficacy of different doses of clodronate in affected patients. PATIENTS AND METHODS: Eighty-four patients with tumor-induced osteolysis were randomized to receive treatment with placebo, or 400 mg, 1,600 mg, or 3,200 mg of clodronate, daily for 4 weeks. Patients were reviewed weekly during treatment. Fasting urinary calcium excretion was the primary variable used to assess response. Visual analog pain scores and adverse events were documented. RESULTS: In the clodronate-treated groups, there was a dose-dependent reduction in fasting calcium excretion with a highly significant difference between placebo and 1,600 mg clodronate (P = .0002) and placebo and 3,200 mg clodronate (P = .0001), but no significant difference between 1,600 mg and 3,200 mg clodronate. There was no discernible change in pain scores or analgesic requirements. Bone-derived isoenzyme alkaline phosphatase values increased in all groups, with a significant difference between baseline and final values in the 1,600-mg and 3,200-mg groups (P < .01 and P = .03, respectively). Adverse events were distributed evenly across the four treatment groups. Compliance was greater than 99% in all treatment groups. CONCLUSION: Oral clodronate at a dose of 1,600 mg or 3,200 mg will inhibit bone resorption. Since there was no significant difference between these two doses in terms of efficacy at 4 weeks, 1,600 mg/d can be recommended for long-term treatment. This dose is well tolerated and may promote bone repair, as judged by increases in bone alkaline phosphatase levels.

Rationale for the use of bisphosphonates in bone metastases.

Neoplasia affecting the skeleton is an important cause of morbidity, which includes hypercalcaemia, bone pain and fracture. In most instances these events are mediated by an increase in the resorption of bone which decreases bone density and disrupts skeletal architecture, either at focal sites or generally throughout the skeleton. Neoplastic activation of bone resorption in heterogeneous, but there is now good evidence that this is due to the increased activation of osteoclasts, the cells which mediate bone resorption in health. Bisphosphonates are specific inhibitors of osteoclast-mediated bone resorption and are capable of inhibiting osteoclastic activation independent of the mechanism of its stimulation. This provides the rationale for the use of bisphosphonates in the hypercalcaemia of malignancy. Despite refinements in the use of endocrine therapy, chemotherapy and radiotherapy these interventions have had relatively little impact on the skeletal morbidity or mortality of common malignancies affecting the skeleton, particularly breast cancer and myelomatosis. In addition, there is good evidence that skeletal disease is progressive in many patients despite the use of chemotherapy and radiotherapy. Since accelerated bone resorption can be inhibited by long-term treatment with bisphosphonates, their use is likely to decrease skeletal complications such as bone pain and fracture. The bisphosphonates, therefore, hold great promise as agents to improve the quality of life of such patients.

Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature.

Lymphomas account for 2-5% of all oral malignancies and are the third most common in this site. This case report appears to be the first in the world literature describing spontaneous regression in the oral cavity of a subset of non-Hodgkins lymphomas known as Ki-1 anaplastic large cell lymphomas (ALCL). Ki-1 ALCL account for 2-7% of all non-Hodgkins lymphomas and the clinical presentation is variable; they may arise de novo or in the setting of a separate primary lymphoma and commonly present in the extra-nodal location. Disease severity is also variable with waxing and waning lesions at one extreme which may spontaneously regress to bone marrow involvement in around 12% of cases. This case is especially interesting since the patient is a farmer, given the recent evidence that there may be a link between non-Hodgkins lymphoma and this occupation.

Response biases as a confound to expressed burden among spousal caregivers of suspected dementia patients.

Burden among family caregivers has yet to be adequately assessed relative to social desirability response sets. This study examined the impact of two different response biases relative to expressed burden among spousal caregivers of suspected dementia patients. In addition to individual social desirability, it was hypothesized that a distinct social desirability construct exists as a function of one's perception of self within relationships. As predicted, a significant inverse association was apparent between expressed burden and this systemic response bias (as measured by the Edmonds Marital Conventionality Scale), whereas this association was not apparent with a measure of individual social desirability (the Marlowe-Crowne Social Desirability Scale). This finding suggests that systemic social desirability may exist as a significant response bias.

The utility of a dilatation and evacuation procedure in patients with symptoms suggestive of ectopic pregnancy and indeterminate transvaginal ultrasonography.

OBJECTIVES: To ascertain the overall frequency of obtaining chorionic villi (CV) in patients with indeterminate transvaginal ultrasound (US) examinations who have had a dilatation and evacuation (D+E) procedure performed, to determine whether the frequency of obtaining CV is dependent on whether the endometrial cavity is empty at US, and to determine the likelihood of ectopic pregnancy in patients without CV after D+E and with or without an empty endometrial cavity at US. METHODS: A retrospective review was made of consecutive ED patients presenting to an urban teaching hospital from August 1991 through August 1997 with abdominal pain or vaginal bleeding and a positive beta-human chorionic gonatropin (beta-hCG) test. Patients who had a transvaginal US that was read as indeterminate (no extrauterine findings of ectopic pregnancy, and no intrauterine fetal pole or yolk sac) and who had a D+E performed within 48 hours of the ED visit were eligible. US exams were subdivided into two groups, those with empty endometrial cavities and those with endometrial cavities that contained fluid, echogenic material, or sac-like structures. The presence or absence of CV was based on the official pathology report. Patients were excluded if pathology results were not available. RESULTS: A total of 255 patients met eligibility criteria. Of these, pathology results were not available for five patients. Of the remaining patients, 177 of 250 (70.8%: 95% CI = 64.7% to 76.3%) had CV identified in the pathology specimen. The difference in the frequencies of obtaining CV in those with empty endometrial cavities (35/78; 44.9%: 95% CI = 34% to 56%) vs. those without empty endometrial cavities (142/172; 82.6%: 95% CI = 76% to 88%) was significant (p<0.001). Ectopic pregnancy was diagnosed in 17 of 42 (40.0%) with empty uteri at US and no CV at pathology vs 5 of 26 (19.2%) in whom the uterus was not empty and no CV were obtained (p = 0.07). CONCLUSION: In symptomatic patients with indeterminate transvaginal ultrasound exams, CV will be identified after D+E in approximately 70% of cases. Although CV were found with increased frequency when the endometrial cavity was not empty, still almost half of the patients with empty uteri had villi identified. Finally, although the frequency of ectopic pregnancy was higher in the patients with empty uteri and no CV at D+E, vs. those without an empty uterus and no CV, this difference did not reach statistical significance.

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.

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.

Lung cancer treatment waiting times and tumour growth.

We report a single-centre prospective audit of 29 lung cancer patients who were awaiting radical (potentially curative) radiotherapy. This was the total number assessed as suitable for radical treatment by one consultant during 1999. At the time of assessment they had been newly diagnosed and staged with a computed tomographic (CT) scan of chest. They had a subsequent CT scan prior to starting treatment for the purpose of planning the radiation fields. We have now measured tumour size on the diagnostic scans and compared this with the size on the planning scans. We have documented the delay between diagnostic and planning CT scanning and the total time between first hospital visit and starting treatment. Two patients had progression of symptoms while on the waiting list, making them unfit for radical treatment, and another four had tumour progression on planning CT such that the tumour volume was too large for radical treatment. Therefore, 21% of potentially curable patients became incurable on the waiting list. The delay between diagnostic and planning CT scans ranged from 18 to 131 days (median 54), with increases in the cross-sectional tumour size over that period ranging zero to 373%. The delay between the first hospital visit and starting treatment was 35-187 days (median 94); between the date of the radiotherapy request and the starting date for treatment it was 23-61 days (median 44). Limited access to specialists is the reason most often advanced for the poor performance of the UK in treating lung cancer. This study demonstrates that, even for the select minority of patients who have specialist referral and are deemed suitable for potentially curative treatment, the outcome is prejudiced by waiting times that allow tumour progression.

Tumour induced hypercalcaemia: a case for active treatment.

This paper reports a retrospective survey of the diagnosis, management and outcome of hypercalcaemia in patients admitted to a regional oncology centre over a 12-month period; 168 cases of tumour induced hypercalcaemia were identified. In 69 patients (41%) the presence of hypercalcaemia was not noted in the case records; in a further 15 patients (9%) a positive decision was made not to treat the condition, although some of these patients continued to receive other forms of active treatment. Of the remaining patients, 20 (12%) received intravenous fluids alone and 64 (38%) received bisphosphonate therapy. Of those patients with initial serum calcium > 3 mmol/l 71% were treated with bisphosphonates. Median survival from onset of hypercalcaemia was only 2 months, but in the bisphosphonate treated group, 98% experienced a fall in serum calcium within a week of treatment. We believe that the symptomatic relief associated with a fall in serum calcium justifies active management even in the face of a poor prognosis. A large proportion of cases of tumour induced hypercalcaemia remain undiagnosed or untreated and we believe that this deserves further attention.

A comparison of alternative approaches to the scoring of clock drawing.

Although a number of scoring procedures for clock drawing have emerged in the literature, no systematic comparison of the psychometric properties of various approaches has yet been conducted on a large sample of persons over 64 years of age diagnosed with dementia or deemed cognitively intact. The present study examined the reliability and validity of five scoring approaches (Doyon, Bouchard, Morin, Bourgeois, & Cote, 1991; Shulman, Shedletsky, & Silver, 1986; Tuokko, Hadjistavropoulos, Miller, & Beattie, 1992; Watson, Arfken, & Birge, 1993; Wolf-Klein, Silverstone, Levy, Brod, & Breuer, 1989) among the 493 participants of the Canadian Study of Health and Aging who completed clock drawing and who had a final diagnosis assigned at the conclusion of a comprehensive clinical examination. Inter- and intra-rater reliabilities were highest for the Tuokko et al. method. The Tuokko and Shulman scoring procedures had the highest sensitivities and relatively low specificities. The Wolf-Klein procedure had relatively low sensitivities and high specificities. Estimated areas under receiver operating curves were relatively high for all scoring methods. However, the area under the curve for the Watson procedure was significantly lower than the other procedures. All claims to the utility of clock drawing for differentiating between normal persons over 64 years of age and those with dementia appear validated.

Early identification of dementia: predictive validity of the clock test.

Various clock scoring procedures have been developed in recent years as dementia screening measures. The current longitudinal study was developed to assess the predictive validity of the Clock Test (Tuokko, Hadjistavropoulos, Miller, Horton, & Beattie, 1995). Within a sample of subjects who initially did not meet dementia criteria, Clock Test scores (drawing, setting, and reading) distinguished between those who later met criteria for dementia as compared to subjects who did not. When impaired performance was identified as falling below cut-off on two or more subtests of the Clock Test, sensitivity and specificity were found to be 91% and 95% relative to time two diagnosis. Clock errors among the current sample were compared against normal control subjects from the Canadian Study of Health and Aging (CSHA). These comparative analyses attest to the relative normality of the clinic sample at the time of their initial assessment.