The PRO-ACTIVE trial protocol: a randomized study comparing the effectiveness of PROphylACTic swallow InterVEntion for patients receiving radiotherapy for head and neck cancer.

BACKGROUND: Swallowing therapy is commonly provided as a treatment to lessen the risk or severity of dysphagia secondary to radiotherapy (RT) for head and neck cancer (HNC); however, best practice is not yet established. This trial will compare the effectiveness of prophylactic (high and low intensity) versus reactive interventions for swallowing in patients with HNC undergoing RT. METHODS: This multi-site, international randomized clinical trial (RCT) will include 952 adult patients receiving radiotherapy for HNC and who are at high risk for post-RT dysphagia. Participants will be randomized to receive one of three interventions for swallowing during RT: RE-ACTIVE, started promptly if/when dysphagia is identified; PRO-ACTIVE EAT, low intensity prophylactic intervention started before RT commences; or, PRO-ACTIVE EAT+EXERCISE, high intensity prophylactic intervention also started before RT commences. We hypothesize that the PRO-ACTIVE therapies are more effective than late RE-ACTIVE therapy; and, that the more intensive PRO-ACTIVE (EAT + EXERCISE) is superior to the low intensive PRO-ACTIVE (EAT). The primary endpoint of effectiveness is duration of feeding tube dependency one year post radiation therapy, selected as a pragmatic outcome valued equally by diverse stakeholders (e.g., patients, caregivers and clinicians). Secondary outcomes will include objective measures of swallow physiology and function, pneumonia and weight loss, along with various patient-reported swallowing-related outcomes, such as quality of life, symptom burden, and self-efficacy. DISCUSSION: Dysphagia is a common and potentially life-threatening chronic toxicity of radiotherapy, and a priority issue for HNC survivors. Yet, the optimal timing and intensity of swallowing therapy provided by a speech-language pathologist is not known. With no clearly preferred strategy, current practice is fraught with substantial variation. The pragmatic PRO-ACTIVE trial aims to specifically address the decisional dilemma of when swallowing therapy should begin (i.e., before or after a swallowing problem develops). The critical impact of this dilemma is heightened by the growing number of young HNC patients in healthcare systems that need to allocate resources most effectively. The results of the PRO-ACTIVE trial will address the global uncertainty regarding best practice for dysphagia management in HNC patients receiving radiotherapy. TRIAL REGISTRATION: The protocol is registered with the US Patient Centered Outcomes Research Institute, and the PRO-ACTIVE trial was prospectively registered at ClinicalTrials.gov , under the identifier NCT03455608 ; First posted: Mar 6, 2018; Last verified: Jun 17, 2021. Protocol Version: 1.3 (January 27, 2020).

Adjuvant platinum-based chemotherapy in non-small cell lung cancer: The role of relative dose-intensity and treatment delay.

BACKGROUND: The study investigated the association of the relative dose-intensity (RDI) of cisplatin and timing of adjuvant platinum-based chemotherapy (APC) with survival for stage I-III non-small cell lung cancer (NSCLC) patients. MATERIAL AND METHODS: Real-life data of patients treated with APC (four cycles of cisplatin and vinorelbine) between 2007 and 2014 was included to analyse the association between disease-free survival (DFS) and overall survival (OS) with RDI (ratio of received to planned dose-intensity). High RDI was defined as cisplatin RDI of > 75% and low RDI ≤ 75%. RESULTS: Out of 198 patients, 166 were eligible. Low RDI was administered to 72 (43%) patients. In multivariate analysis, those patients had a significantly higher risk of recurrence (HR: 1.87, 95%CI 1.13-3.09, p = 0.01) and death (HR: 1.91, 95%CI 1.32-3.23, p = 0.01) versus patients in the high RDI group. The risk of death was significantly higher in patients with PS 1 treated with low versus high RDI (HR: 2.72, 95%CI: 1.22-6.09, p = 0.014). The risk of recurrence was higher for patients with squamous cell carcinoma of low versus high RDI (HR: 3.82, 95%CI: 1.01-14.4, p = 0.048). No impact of delayed APC beyond six weeks from surgery on neither DFS (HR: 0.78, 95%CI: 0.46-1.33, p = 0.36) nor OS (HR 0.67, 95%CI: 0.40-1.15, p = 0.15) was observed. CONCLUSION: Low cisplatin RDI ≤ 75% of APC, but not extended time from surgery to APC onset > six weeks, was associated with significantly shorter survival in NSCLC patients.

Soft tissue head and neck sarcoma: experience of a tertiary referral centre over a 15-year period.

BACKGROUND: Head and neck soft tissue sarcoma is uncommon. It is both histologically and clinically heterogeneous, ranging from an indolent, locally destructive tumour, to a locally aggressive neoplasm with metastatic potential. METHODS: A retrospective review was conducted of all adult head and neck soft tissue sarcomas, including cases of malignant soft tissue sarcoma and all intermediate type tumours, diagnosed between 1997 and 2012. RESULTS: Sixty-eight cases were identified in this series from the sarcoma multidisciplinary team. Seventeen different histological subtypes of sarcoma were identified. Neither age, gender nor tumour size were significant prognostic indicators for survival in this series. CONCLUSION: Prognosis is dependent on histological subtype, underscoring the importance of histological classification. Some histological subtypes occur only once or twice in a decade, even within a large regional referral centre. An accumulation of evidence from relatively small case series is key in the long-term development of treatment strategies.

Fractional exhaled nitric oxide as a potential biomarker for radiation pneumonitis in patients with non-small cell lung cancer: A pilot study.

INTRODUCTION: The aim of the study was to investigate repetitive fractional exhaled nitric oxide (FeNO) measurements during high-dose radiation therapy (HDRT) and to evaluate the use of FeNO to predict symptomatic radiation pneumonitis (RP) in patients being treated for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 50 patients with NSCLC referred for HDRT were enrolled. FeNO was measured at baseline, weekly during HDRT, one month- and every third month after HDRT for a one-year follow-up period. The mean FeNO(visit 0-6) was calculated using the arithmetic mean of the baseline and weekly measurements during HDRT. Patients with grade ≥ 2 of RP according to the Common Terminology Criteria for Adverse Events (CTCAE) were considered symptomatic. RESULTS: A total of 42 patients completed HDRT and weekly FeNO measurements. Grade ≥ 2 of RP was diagnosed in 24 (57%) patients. The mean FeNO(visit 0-6) ±â€¯standard deviation in patients with and without RP was 15.0 ±â€¯7.1 ppb (95%CI: 12.0-18.0) and 10.3 ±â€¯3.4 ppb (95%CI: 8.6-11.9) respectively with significant differences between the groups (p = 0.0169, 95%CI: 2.3-2.6). The leave-one-out cross-validated cut-off value of the mean FeNO(visit 0-6) ≥ 14.8 ppb was predictive of grade ≥ 2 RP with a specificity of 71% and a positive predictive value of 78%. CONCLUSIONS: The mean FeNO(visit 0-6) in patients with symptomatic RP after HDRT for NSCLC was significantly higher than in patients without RP and may serve as a potential biomarker for RP.

Identification of swallowing disorders in early and mid-stage Parkinson's disease using pattern recognition of pharyngeal high-resolution manometry data.

BACKGROUND: Parkinson's disease (PD) can cause severe dysphagia, especially later in disease progression. Early identification of swallowing dysfunction may lead to earlier intervention. Pharyngeal high-resolution manometry (HRM) provides complementary information to videofluoroscopy, with advantages of being quantitative and objective. Artificial neural network (ANN) classification can examine non-linear relationships among multiple variables with relatively low bias. We evaluated if ANN techniques could differentiate between patients with PD and healthy controls. METHODS: Simultaneous videofluoroscopy and pharyngeal HRM were performed on 31 patients with early to mid-stage PD and 31 age- and sex-matched controls during thin-liquid swallows of 2 cc, 10 cc and comfortable sip volume. We performed multilayer-perceptron analyses on only videofluoroscopic data, only HRM data or a combination of the two. We also evaluated variability-based parameters, representing variability in manometric parameters across multiple swallows. We hypothesized that patients with PD and controls would be classified with at least 80% accuracy, and that combined videofluoroscopic and HRM data would classify participants better than either alone. KEY RESULTS: Classification rates were highest with all parameters considered. Maximum classification rate was 82.3 ± 5.2%, recorded for 2 cc swallows. Inclusion of variability-based parameters improved classification rates. Classification rates using only manometric parameters were similar to those using all parameters, and rates were substantially lower for the comfortable sip volumes. CONCLUSIONS & INFERENCES: Results from these classifications highlight the differences between swallowing function in patients with early and mid-stage PD and healthy controls. Early identification of swallowing dysfunction is key to developing preventative swallowing treatments for those with PD.

Extra-abdominal desmoid fibromatosis: A review of management, current guidance and unanswered questions.

Extra abdominal desmoid fibromatosis is a complex condition with many recognised treatments including active observation, hormonal therapy, chemotherapy, radiotherapy and surgical resection. There is large variation in the natural history of individual desmoid tumours, with some cases progressing aggressively and others regressing spontaneously when observed alone. This combined with an absence of accurate clinical predictors of a desmoid tumour's behaviour has led to difficulties in identifying which patients would benefit most from aggressive treatment, and which could be adequately managed with a policy of active observation alone. This review explores the aetiology and common presentation of extra-abdominal desmoid fibromatosis including the condition's histopathological, clinical and radiological characteristics. The current evidence for potential predictors of desmoid tumour behaviour is also reviewed, along with the indications and evidence for the multitude of treatments available. We also summarise the published guidelines that are currently available for oncologists and surgeons managing extra-abdominal desmoid fibromatosis, and highlight some of the unanswered questions that need to be addressed to optimise the management of this condition.

The biological response to a failed extra-articular polyester ligament used for AC Joint reconstruction at the shoulder girdle: a retrieval analysis of five cases.

The LockDown device (previously called Surgilig) is a braided polyester mesh which is mostly used to reconstruct the dislocated acromioclavicular joint. More than 11,000 have been implanted worldwide. Little is known about the tissue reaction to the device nor to its wear products when implanted in an extra-articular site in humans. This is of importance as an adverse immunological reaction could result in osteolysis or damage to the local tissues, thereby affecting the longevity of the implant. We analysed the histology of five LockDown implants retrieved from five patients over the last seven years by one of the senior authors. Routine analysis was carried out in all five cases and immunohistochemistry in one. The LockDown device acts as a scaffold for connective tissue which forms an investing fibrous pseudoligament. The immunological response at the histological level seems favourable with a limited histiocytic and giant cell response to micron-sized wear particles. The connective tissue envelope around the implant is less organised than a native ligament.

Extra-abdominal desmoid fibromatosis--a sarcoma unit review of practice, long term recurrence rates and survival.

INTRODUCTION: Desmoid fibromatosis (DF) carries a significant morbidity and a recognised mortality. Despite this there are currently limited diagnostic or treatment algorithms specific to cases of extra-abdominal DF. Historically surgical excision has formed the cornerstone of treatment. Recently however a paradigm shift has meant many practitioners now adopt a more conservative approach, placing emphasis on active surveillance, function preserving resections, and non-surgical oncologic therapies. METHODS: We performed an 8-year retrospective review of all cases of extra-abdominal DF managed within our region to assess the consistency of diagnostics, management and long-term outcome. RESULTS: 47 eligible cases were identified. Mean age at diagnosis was 41.3 years (1-81 years). Disease location and speciality of diagnosing practitioners were varied. Management was generally inconsistent. Variation was seen in imaging, biopsy techniques, MDT involvement and management. At a median follow up of 4.9 years our local recurrence rate was 19%. DISCUSSION: The optimal management of DF is unknown. This has led to a lack of formalised guidance for practitioners managing this challenging condition, resulting in inconsistencies and areas for improvement in current management. We propose a diagnostic pathway which may improve consistency of care, reduce potentially unnecessary surgery and the associated morbidity, and significantly increase the rate of complete (R0) surgical resections when surgery is deemed appropriate whilst not significantly worsening oncological outcome. Specifically we propose all cases should be imaged appropriately (usually with MRI), undergo a planned biopsy (by radiologically guided core needle biopsy) and be managed centrally in conjunction with multidisciplinary sarcoma units.

Tumour-to-tumour metastasis of laryngeal leiomyosarcoma to an axillary hibernoma.

Tumour-to-tumour metastasis is a rare, but well-recognised occurrence. This case report documents the metastasis of a primary laryngeal leiomyosarcoma to a hibernoma. We believe that this is the first recorded case of leiomyosarcoma metastasising to another neoplasm, and the first recorded case of a hibernoma acting as a recipient tumour for metastasis. This case study emphasises the importance of re-imaging a known benign mass in the presence of new symptoms in a patient with underlying malignancy, to ensure prompt diagnosis and management of potentially treatable metastasis. The imaging findings including whole body magnetic resonance imaging (MRI) staging, macroscopic and histological features are presented.

A multi-centre analysis of the impact of updated risk stratification on follow-up of gastric gastro-intestinal stromal tumours in the post-imatinib era.

BACKGROUND: Previously Gastro-Intestinal Stromal Tumours (GISTs) have been risk stratified histologically according to their size and mitotic index. However, gastric GISTs have a lower likelihood of recurrence and so the Miettinen criteria are now used to risk stratify patients. Records were reviewed from multiple centres to determine if these changes altered patients' clinical care and also to determine the survival of patients following the introduction of imatinib therapy. METHODS: Prospective databases of GISTs undergoing surgical resection and those reviewed by the regional sarcoma MDT were cross-referenced and added to by searching a variety of clinical and pathology coding datasets, to identify patients diagnosed between January 2000 and March 2010. Patients undergoing resection for localised disease were re-scored using Miettinen criteria and Kaplan-Meier analysis was used to determine survival outcomes. RESULTS: The search identified 203 patients; including 132 gastric GISTs, 89 of which had resections of untreated localised disease. These were reassessed, of which approximately one third were scored as intermediate risk. Following reclassification, 26 of 29 of intermediate risk cases moved to low risk groups, representing 27.7% of all those remaining in follow-up at the time of audit. Median survival was not reached after a median follow-up of 3.85 years and 4-year survival was estimated at 72%. CONCLUSIONS: Clinicians involved in the follow-up of gastric GISTs should reassess the pathology of all intermediate and high risk patients in order to decrease patient exposure to stressful interventions, as well as hospital workload, and expenditure on unnecessary observation.

Inadvertent surgical resection of soft tissue sarcomas.

BACKGROUND: The National Institute of Clinical Excellence (NICE) published Improving Outcome Guidance in 2006 defining urgent referral criteria for soft tissue sarcoma (STSs) with the twin aims of improving diagnostic accuracy and overall outcome. Despite these guidelines inadvertent excisions of soft tissue sarcomas continue to occur with alarming frequency, potentially compromising patient outcomes. OBJECTIVE: We reviewed the East Midlands Sarcoma Service experience of treating inadvertent excision of STSs and highlight the patient profile, referral pattern, subsequent management and oncological outcome associated with inadvertent resection. METHODS: Patients were identified from our sarcoma database and a retrospective case note review performed. RESULTS: Over a 3-year period, 42 patients presented to our specialist centre after unplanned excision of soft tissue sarcomas. There were 29 men and 13 women, with a mean age at presentation of 59 years (19-90). 50% of the tumours were located in lower extremity, 33% around the trunk and 17% in the upper extremity. The unplanned surgery was most commonly from general surgeons, plastic surgeons, orthopaedic surgeons, general practitioners followed by vascular surgeons. Re-resection was undertaken in 40 cases to achieve clear margins with residual tumour present in 74% of cases. Limb salvage surgery was not possible in 5 cases. CONCLUSION: Unplanned excision of sarcoma by non-oncologic surgeons remains a problem. It appears that it is equally prevalent in varied surgical community and general practitioners. Excision of large or deep solid soft tissue masses without tissue diagnosis is unacceptable.

Relative hypotension in the beach-chair position: effects on middle cerebral artery blood velocity.

When anaesthetising patients for arthroscopic shoulder surgery, it is common practice to sit the patient in the beachchair position and to optimise arthroscopy by allowing relative hypotension. There is little published information regarding the cerebral haemodynamic effects of hypotension in the sitting position during general anaesthesia. In this study, 19 patients scheduled for shoulder surgery were anaesthetised with desflurane. Phenylephrine and/or remifentanil were used to control blood pressure. Cerebral haemodynamics were assessed by monitoring middle cerebral artery blood velocity with transcranial Doppler, and by invasive arterial pressure monitoring with the transducer kept level with the external auditory meatus. Pressure and velocity waveforms were analysed to calculate apparent zero flow pressure and resistance area product. Cerebral haemodynamics in patients anaesthetised supine at the pre-induction blood pressure were compared with haemodynamics while seated at 45 degrees with hypotension. According to our routine practice, blood pressure management was guided by non-invasive measurement of systolic pressure using an arm cuff Changing from supine/normotensive to sitting/hypotensive caused mean arterial pressure at the auditory meatus to decrease 47 +/- 7% and middle cerebral artery blood velocity to decrease 22 +/- 7%. In the beach-chair position, systolic pressure was 96 +/- 10 mmHg in the arm and 76 +/- 10 mmHg at the auditory meatus (P < 0.0001). Both resistance area product and apparent zero flow pressure decreased, suggesting decreases in cerebrovascular resistance and critical closing pressure. Although there was some evidence of an autoregulatory response, middle cerebral artery blood velocity decreased when relative hypotension was induced in patients anaesthetised with desflurane in the beach-chair position.