Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial.

PURPOSE: Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer. METHODS AND MATERIALS: Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed. RESULTS: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. CONCLUSIONS: CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

Paraquat ingestion in an adult with cystic fibrosis (CF): Diagnostic and management dilemmas.

N,N'-dimethyl-4,4'bipyridinium dichloride (Paraquat) is a potent herbicide used widely in agriculture. We report the effects of an ingestion of paraquat by a 28 year old male with cystic fibrosis and the diagnostic and management challenges this posed in both the acute and longer term setting. We describe the effects of direct paraquat toxicity on the lung tissue secondary to aspiration and review the long-term sequelae of paraquat, namely osteonecrosis. Our case is the first to describe osteonecrosis of the knee in the context of paraquat toxicity. Survival following ingestion remains poor with a high associated mortality. However, timely treatment with NAC and immunosuppression may impact on survival. In those patients who do survive the acute phase post ingestion, follow-up over years may be required to detect the long-term effects of paraquat on bone health.

TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.

MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.

Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.

Cohort study of sleep quality in adult patients with acute pulmonary exacerbations of cystic fibrosis.

BACKGROUND: The impact of an acute pulmonary exacerbation of cystic fibrosis (CF) on sleep quality has not been established. Patients have greater burden of symptoms, higher intensity of therapy and are often admitted to hospital outside of their usual sleeping environment. AIMS: To evaluate the prevalence of, and factors associated with, poor sleep quality in adult patients admitted to hospital with an acute exacerbation of CF lung disease. METHODS: This prospective, observational study determined the prevalence of impaired sleep quality and associated factors in adult patients admitted to a single CF unit with an acute pulmonary exacerbation of CF. Sleep quality was defined by the Pittsburgh Sleep Quality Index (PSQI), with >5 indicating poor sleep quality. Data were obtained through patient questionnaires, chart review and examination. RESULTS: Sixty-six percent of patients had impaired sleep quality. Patients with poor sleep had more sleep disruption due to pain (median response 'mild sleep disruption' vs 'no sleep disruption'; P = 0.003) and insomnia (mean Insomnia Severity Index (ISI) 13 vs 5; P < 0.001). In patients with symptoms of restless legs, poor sleepers had worse symptoms (mean International Restless Legs Severity Score (IRLSS) 15 vs 5; P = 0.029). Univariate modelling showed relationships between PSQI and symptoms of depression and anxiety as well as with sleep disruption due to pain, general noise and nursing observations. In a multivariable model, ISI was the only variable that remained significantly associated with PSQI. Mean PSQI score increased 0.58 units for each 1 unit increase in ISI (95% CI 0.42-0.73; P < 0.001). CONCLUSIONS: Poor sleep quality is common among patients admitted with an acute exacerbation of CF and is strongly associated with insomnia symptoms in this cohort.

Atrophy patterns in isolated subscapularis lesions.

BACKGROUND: While supraspinatus atrophy can be described according to the system of Zanetti or Thomazeau there is still a lack of characterization of isolated subscapularis muscle atrophy. The aim of this study was to describe patterns of muscle atrophy following repair of isolated subscapularis (SSC) tendon. METHODS: Forty-nine control shoulder MRI scans, without rotator cuff pathology, atrophy or fatty infiltration, were prospectively evaluated and subscapularis diameters as well as cross sectional areas (complete and upper half) were assessed in a standardized oblique sagittal plane. Calculation of the ratio between the upper half of the cross sectional area (CSA) and the total CSA was performed. Eleven MRI scans of patients with subscapularis atrophy following isolated subscapularis tendon tears were analysed and cross sectional area ratio (upper half /total) determined. To guarantee reliable measurement of the CSA and its ratio, bony landmarks were also defined. All parameters were statistically compared for inter-rater reliability, reproducibility and capacity to quantify subscapularis atrophy. RESULTS: The mean age in the control group was 49.7 years (± 15.0). The mean cross sectional area (CSA) was 2367.0 mm2 (± 741.4) for the complete subscapularis muscle and 1048.2 mm2 (± 313.3) for the upper half, giving a mean ratio of 0.446 (± 0.046). In the subscapularis repair group the mean age was 56.7 years (± 9.3). With a mean cross sectional area of 1554.7 mm2 (± 419.9) for the complete and of 422.9 mm2 (± 173.6) for the upper half of the subscapularis muscle, giving a mean CSA ratio of 0.269 (± 0.065) which was seen to be significantly lower than that of the control group (p < 0.05). CONCLUSION: Analysis of typical atrophy patterns of the subscapularis muscle demonstrates that the CSA ratio represents a reliable and reproducible assessment tool in quantifying subscapularis atrophy. We propose the classification of subscapularis atrophy as Stage I (mild atrophy) in case of reduction of the cross sectional area ratio < 0.4, Stage II (moderate atrophy) in case of < 0.35 and Stage III (severe atrophy) if < 0.3.

Stereotactic radiotherapy with focal boost for intermediate and high-risk prostate cancer: Initial results of the SPARC trial.

INTRODUCTION: Dose escalation to dominant intraprostatic lesions (DILs) is a novel method to increase the therapeutic ratio in localised prostate cancer. The Stereotactic Prostate Augmented Radiotherapy with Cyberknife (SPARC) trial was designed to determine the feasibility of a focal boost defined with multiparametric magnetic resonance imaging (mpMRI) using stereotactic ablative body radiotherapy (SABR). MATERIALS AND METHODS: Patients were included with newly diagnosed intermediate to high risk prostate cancer with at least one of: Gleason score 4 + 3, stage T3a, or PSA > 20 ng/ml. Visible disease on mpMRI was mandatory and up to 2 separate nodules were allowed. All patients received androgen deprivation. Patients received 36.25 Gy in 5 fractions using CyberKnife® and the DIL received a simultaneous boost to a maximum of 47.5 Gy, as allowed by OAR constraints. Genitourinary (GU) and gastrointestinal (GI) toxicity was reported using the RTOG scoring criteria. International Index of Erectile Function (IIEF) and EQ-5D global health scores were regularly captured. RESULTS: An interim safety analysis was performed on the first 8 patients, recruited between July 2013 and December 2015. Median follow up was 56 months (range 50-74). Median D95 values for the prostate PTV and boost volume were 36.55 Gy (range 35.87-36.99) and 46.62 Gy (range 44.85-48.25) respectively. Of the dose constraints, 10/80 were not achieved but all were minor dose variations. Grade 2+ acute GU and GI toxicities were 37.5% respectively while grade 2+ late GU and GI toxicities were 12.5% and 0% respectively. IIEF and quality of life scores recovered over time and all patients remain in biochemical remission. CONCLUSION: The first patients have been successfully treated with prostate SABR and focal boost on the SPARC trial, with excellent adherence to the planning protocol. Toxicity and efficacy results are promising and further recruitment is underway.

CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma.

Despite remarkable success in the treatment of hematological malignancies, CAR T-cell therapies for solid tumors have floundered, in large part due to local immune suppression and the effects of prolonged stimulation leading to T-cell dysfunction and exhaustion. One mechanism by which gliomas and other cancers can hamper CAR T cells is through surface expression of inhibitory ligands such as programmed cell death ligand 1 (PD-L1). Using the CRIPSR-Cas9 system, we created universal CAR T cells resistant to PD-1 inhibition through multiplexed gene disruption of endogenous T-cell receptor (TRAC), beta-2 microglobulin (B2M) and PD-1 (PDCD1). Triple gene-edited CAR T cells demonstrated enhanced activity in preclinical glioma models. Prolonged survival in mice bearing intracranial tumors was achieved after intracerebral, but not intravenous administration. CRISPR-Cas9 gene-editing not only provides a potential source of allogeneic, universal donor cells, but also enables simultaneous disruption of checkpoint signaling that otherwise impedes maximal antitumor functionality.

Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.

Functional improvements in active elevation, external rotation, and internal rotation after reverse total shoulder arthroplasty with isolated latissimus dorsi transfer: surgical technique and midterm follow-up.

HYPOTHESIS: This study investigated the hypothesis that reverse total shoulder arthroplasty (RSA) in combination with an isolated latissimus dorsi tendon (LDT) transfer in patients with pseudoparalysis of abduction and external rotation (combined loss of active elevation and external rotation [CLEER] syndrome) would demonstrate improved postoperative functional results. METHODS: This study was a retrospective single-surgeon case series of 13 consecutive patients with CLEER who underwent RSA without subscapularis repair and combined with an isolated LDT transfer. We reviewed 10 patients (77%), at a minimum of 2 years, with 3 cases lost to follow-up. Shoulder function was assessed preoperatively and postoperatively using the Constant score and postoperatively using the Oxford Shoulder Score, University of California-Los Angeles score, American Shoulder and Elbow Surgeons score, ADLEIR (activities of daily living [ADLs] requiring active external and internal rotation) score, and ADLIR (ADLs requiring active internal rotation) score. Force in internal rotation (IR) at 0° of abduction, external rotation (ER) at 0° of abduction, and ER at 90° of abduction, as well as IR in the belly-press position, was measured. RESULTS: The mean postoperative follow-up period was 57 months (range, 31-85 months). We observed improvement in the Constant score (from 29.8 ± 6.64 preoperatively to 71.9 ± 10.45 postoperatively, P < .05), as well as abduction force, ER, and forward elevation (P < .05). Postoperatively, the mean American Shoulder and Elbow Surgeons score was 95.1 ± 3.38 and the mean Oxford Shoulder Score was 46.6 ± 1.57. Mean force in IR at 0° of abduction was 5.45 ± 2.42 kg, and mean force in ER at 90° of abduction was 4 ± 1.20 kg. Mean force in ER at 0° of abduction (3.65 ± 1.24 kg) and IR in the belly-press position (4.5 ± 2.84 kg) demonstrated a positive correlation with ADLs. CONCLUSIONS: The results of this study demonstrate that RSA without subscapularis repair, combined with an isolated LDT transfer, provides improved postoperative functional outcomes for patients with CLEER while maintaining sufficiently balanced force in IR and ER to effectively perform ADLs.

Utility of Multi-Parametric Quantitative Magnetic Resonance Imaging for Characterization and Radiotherapy Response Assessment in Soft-Tissue Sarcomas and Correlation With Histopathology.

Purpose: To evaluate repeatability of quantitative multi-parametric MRI in retroperitoneal sarcomas, assess parameter changes with radiotherapy, and correlate pre-operative values with histopathological findings in the surgical specimens. Materials and Methods: Thirty patients with retroperitoneal sarcoma were imaged at baseline, of whom 27 also underwent a second baseline examination for repeatability assessment. 14/30 patients were treated with pre-operative radiotherapy and were imaged again after completing radiotherapy (50.4 Gy in 28 daily fractions, over 5.5 weeks). The following parameter estimates were assessed in the whole tumor volume at baseline and following radiotherapy: apparent diffusion coefficient (ADC), parameters of the intra-voxel incoherent motion model of diffusion-weighted MRI (D, f, D*), transverse relaxation rate, fat fraction, and enhancing fraction after gadolinium-based contrast injection. Correlation was evaluated between pre-operative quantitative parameters and histopathological assessments of cellularity and fat fraction in post-surgical specimens (ClinicalTrials.gov, registration number NCT01902667). Results: Upper and lower 95% limits of agreement were 7.1 and -6.6%, respectively for median ADC at baseline. Median ADC increased significantly post-radiotherapy. Pre-operative ADC and D were negatively correlated with cellularity (r = -0.42, p = 0.01, 95% confidence interval (CI) -0.22 to -0.59 for ADC; r = -0.45, p = 0.005, 95% CI -0.25 to -0.62 for D), and fat fraction from Dixon MRI showed strong correlation with histopathological assessment of fat fraction (r = 0.79, p = 10-7, 95% CI 0.69-0.86). Conclusion: Fat fraction on MRI corresponded to fat content on histology and therefore contributes to lesion characterization. Measurement repeatability was excellent for ADC; this parameter increased significantly post-radiotherapy even in disease categorized as stable by size criteria, and corresponded to cellularity on histology. ADC can be utilized for characterizing and assessing response in heterogeneous retroperitoneal sarcomas.

Locking nail versus locking plate for proximal humeral fracture fixation in an elderly population: a prospective randomised controlled trial.

BACKGROUND: Proximal humeral fractures (PHFs) are the third most common fracture in older patients. The purpose of the study was to prospectively evaluate the outcomes of PHF fixation with a locking blade nail (LBN) or locking plate (PHILOS) osteosynthesis in a homogeneous elderly patient population. METHODS: Inclusion criteria were an age > 60 years and the capacity to give informed consent. Patients with isolated tuberosity fractures, previous trauma or surgery, advanced osteoarthritis, fracture dislocation, pathological fractures, open fractures, neurological disorders, full-thickness rotator cuff tears, fracture line at the nail entry point or severely reduced bone quality intra-operatively were excluded. Eighty one patients with PHFs were randomised to treatment using LBN or PHILOS. Outcome measures comprised Constant score, age and gender adjusted Constant score, DASH score, VAS for pain, subjective overall condition of the shoulder (1-6) and active shoulder range-of-motion in flexion and abduction. Plain radiographs were obtained in two planes. All data were collected by an independent observer at 3, 6 and 12 months postoperatively. RESULTS: Thirteen patients were excluded intra-operatively due to rotator cuff tears, fracture morphology or poor bone-quality. Of the remaining 68 patients, 27 in the LBN and 28 in the PHILOS group completed the full follow-up. Mean age at surgery was 75.6 years and the majority of PHFs were three-part fractures (49 patients). Baseline demographics between groups were comparable. All outcome measures improved between assessments (p < 0.001). The LBN group showed improved DASH scores as compared to PHILOS at 12 months (p = 0.042) with fewer incidences of secondary loss of reduction and screw cut-out (p = 0.039). A total of 29 complications (in 23 patients) were recorded, 13 complications (in 12 patients) in the LBN group and 16 complications (in 11 patients) in the PHILOS group (p = 0.941). No significant inter-group difference was observed for any other outcome measures, nor was fracture morphology seen to be associated with clinical outcome or complication rate. CONCLUSIONS: At short-term follow-up, LBN osteosynthesis yielded similar outcomes and complication rates to PHILOS plate fracture fixation in an elderly patient population, though with a significantly lower rate of secondary loss of reduction and screw cut-out. REGISTRATION TRIAL: No. DRKS00015245 at Deutsches Register Klinischer Studien, registered: 22.08.2018, retrospectively registered.

Dosimetric Implications of Computerised Tomography-Only versus Magnetic Resonance-Fusion Contouring in Stereotactic Body Radiotherapy for Prostate Cancer.

Background: Magnetic resonance (MR)-fusion contouring is the standard of care in prostate stereotactic body radiotherapy (SBRT) for target volume localisation. However, the planning computerised tomography (CT) scan continues to be used for dose calculation and treatment planning and verification. Discrepancies between the planning MR and CT scans may negate the benefits of MR-fusion contouring and it adds a significant resource burden. We aimed to determine whether CT-only contouring resulted in a dosimetric detriment compared with MR-fusion contouring in prostate SBRT planning. Methods: We retrospectively compared target volumes and SBRT plans for 20 patients treated clinically with MR-fusion contouring (standard of care) with those produced by re-contouring using CT data only. Dose was 36.25 Gy in 5 fractions. CT-only contouring was done on two occasions blind to MR data and reviewed by a separate observer. Primary outcome was the difference in rectal volume receiving 36 Gy or above. Results: Absolute target volumes were similar: 63.5 cc (SD ± 27.9) versus 63.2 (SD ± 26.5), Dice coefficient 0.86 (SD ± 0.04). Mean difference in apex superior-inferior position was 1.1 (SD ± 3.5; CI: −0.4–2.6). Small dosimetric differences in favour of CT-only contours were seen, with the mean rectal V36 Gy 0.3 cc (95% CI: 0.1–0.5) lower for CT-only contouring. Conclusions: Prostate SBRT can be successfully planned without MR-fusion contouring. Consideration can be given to omitting MR-fusion from the prostate SBRT workflow, provided reference to diagnostic MR imaging is available. Development of MR-only work flow is a key research priority to gain access to the anatomical fidelity of MR imaging.

Arthroscopic Repair of Subscapularis Tendon Tears.

The subscapularis is the largest and strongest muscle of the rotator cuff, and it plays an essential role in global shoulder function. Beyond its primary function as an internal rotator, the subscapularis also acts to pull the humeral head posteriorly on the glenoid and is an important dynamic and static anterior stabilizer of the glenohumeral joint. In comparison with tears of the tendons of the rest of the rotator cuff, isolated tears of the subscapularis have a tendency for both early retraction and fatty infiltration. Consequently, full-thickness tears of the subscapularis tendon generally require surgical management. Arthroscopic suture-anchor repair allows anatomic reconstruction of the anterior aspect of the rotator cuff, with all of the benefits of arthroscopic surgery. The principal steps of this procedure include (1) verifying the subscapularis tear and identifying any concomitant lesions during diagnostic arthroscopy, (2) exposing the subscapularis tendon, (3) releasing tendon adhesions and so enabling anatomic reduction, (4) placing suture anchors at the anatomic subscapularis footprint on the lesser tuberosity and anatomically repairing the subscapularis tendon to its anatomic insertion, and (5) performing biceps tenodesis or tenotomy, if indicated. Postoperatively, patients with an isolated subscapularis tear are managed with immobilization in a sling for 6 weeks, while those with combined anterosuperior rotator cuff tears are managed with an abduction pillow. Arthroscopic subscapularis reconstruction provides a good structural repair, substantially restores shoulder mobility and strength, reduces pain, and results in high levels of patient satisfaction and return of shoulder function as measured by functional outcome scores.

Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort.

BACKGROUND: In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. OBJECTIVE: To determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: A subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18-24 mo and then every 24 mo, with regular PSA measurement. INTERVENTION: Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. RESULTS AND LIMITATIONS: The median follow-up was 9.5 yr (interquartile range 7.9-10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17-3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49-4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0-11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5-6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14-1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70-0.88). The number of variables included in the multivariate model was limited by sample size. CONCLUSIONS: Long-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. PATIENT SUMMARY: Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis.

UNLABELLED: The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PATIENT SUMMARY: This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.

Laparoscopic entry techniques.

BACKGROUND: Laparoscopy is a common procedure in many surgical specialities. Complications arising from laparoscopy are often related to initial entry into the abdomen. Life-threatening complications include injury to viscera e.g. the bowel or bladder, or to vasculature e.g. major abdominal and anterior abdominal wall vessels. Minor complications can also occur, such as postoperative wound infection, subcutaneous emphysema, and extraperitoneal insufflation. There is no clear consensus as to the optimal method of laparoscopic entry into the peritoneal cavity. OBJECTIVES: To evaluate the benefits and risks of different laparoscopic entry techniques in gynaecological and non-gynaecological surgery. SEARCH METHODS: This updated review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group. In addition, MEDLINE, EMBASE, CENTRAL and PsycINFO were searched through to September 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which one laparoscopic entry technique was compared with another. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias, and extracted data. We expressed findings as Peto odds ratios (Peto ORs) with 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of evidence for the main comparisons using GRADE methods. MAIN RESULTS: The review included 46 RCTs including three multi-arm trials (7389 participants) and evaluated 13 laparoscopic entry techniques. Overall there was no evidence of advantage using any single technique for preventing major vascular or visceral complications. The evidence was generally of very low quality; the main limitations were imprecision and poor reporting of study methods. Open-entry versus closed-entry There was no evidence of a difference between the groups for vascular (Peto OR 0.14, 95% CI 0.00 to 6.82, three RCTs, n = 795, I(2) = n/a; very low quality evidence) or visceral injury (Peto OR 0.61, 95% CI 0.06 to 6.08, three RCTs, n = 795, I(2) = 0%; very low quality evidence). There was a lower risk of failed entry in the open-entry group (Peto OR 0.16, 95% CI 0.04 to 0.63, n = 665, two RCTs, I(2) = 0%; very low quality evidence). This suggests that for every 1000 patients operated on, 31 patients in the closed-entry group will have failed entry compared to between 1 to 20 patients in the open-entry group. No events were reported in any of the studies for mortality, gas embolism or solid organ injury. Direct trocar versus Veress needle entry There was a lower risk of vascular injury in the direct trocar group (Peto OR 0.13, 95% CI 0.03 to 0.66, five RCTs, n = 1522, I(2) = 0%; low quality evidence) and failed entry (Peto OR 0.21, 95% CI 0.14 to 0.30, seven RCTs, n = 3104; I ²= 0%; moderate quality evidence). This suggests that for every 1000 patients operated on, 8 patients in the Veress needle group will experience vascular injury compared to between 0 to 5 patients in the direct trocar group; and that 64 patients in the Veress needle group will experience failed entry compared to between 10 to 20 patients in the direct trocar group. The vascular injury significance is sensitive to choice of statistical analysis and may be unreliable. There was no evidence of a difference between the groups for visceral (Peto OR 1.02, 95% CI 0.06 to 16.24, four RCTs, n = 1438, I(2) = 49%; very low quality evidence) or solid organ injury (Peto OR 0.16, 95% Cl 0.01 to 2.53, two RCTs, n = 998, I(2) = n/a; very low quality evidence). No events were recorded for mortality or gas embolism. Direct vision entry versus Veress needle entry There was no evidence of a difference between the groups in the rates of visceral injury (Peto OR 0.15, 95% CI 0.01 to 2.34, one RCT, n = 194; very low quality evidence). Other primary outcomes were not reported. Direct vision entry versus open-entry There was no evidence of a difference between the groups in the rates of visceral injury (Peto OR 0.13, 95% CI 0.00 to 6.50, two RCTs, n = 392; low quality evidence), solid organ injury (Peto OR 6.16, 95% CI 0.12 to 316.67, one RCT, n = 60, I(2) = n/a; very low quality evidence), or failed entry (Peto OR 0.40, 95% CI 0.04 to 4.09, one RCT, n = 60; low quality evidence). Vascular injury was reported, however no events occurred. Our other primary outcomes were not reported. Radially expanding (STEP) trocars versus non-expanding trocars There was no evidence of a difference between the groups for vascular injury (Peto OR 0.24, 95% Cl 0.05 to 1.21, two RCTs, n = 331, I(2) = 0%; low quality evidence), visceral injury (Peto OR 0.13, 95% CI 0.00 to 6.37, two RCTs, n = 331, I(2) = n/a; low quality evidence), or solid organ injury (Peto OR 1.05, 95% CI 0.07 to 16.91, one RCT, n = 244; very low quality evidence). Other primary outcomes were not reported. Comparisons of other laparoscopic entry techniquesThere was a higher risk of failed entry in the group in which the abdominal wall was lifted before Veress needle insertion than in the not-lifted group (Peto OR 4.44, 95% CI 2.16 to 9.13, one RCT, n = 150; very low quality evidence). There was no evidence of a difference between the groups in rates of visceral injury or extraperitoneal insufflation. The studies had small numbers and excluded many patients with previous abdominal surgery, and women with a raised body mass index. These patients may have unusually high complication rates. AUTHORS' CONCLUSIONS: Overall, there is insufficient evidence to recommend one laparoscopic entry technique over another.An open-entry technique is associated with a reduction in failed entry when compared to a closed-entry technique, with no evidence of a difference in the incidence of visceral or vascular injury.An advantage of direct trocar entry over Veress needle entry was noted for failed entry and vascular injury. The evidence was generally of very low quality with small numbers of participants in most studies; our findings should be interpreted with caution.