The effect of manual therapy on ankle dorsiflexion range of motion: A pilot crossover randomized trial.

INTRODUCTION: Restricted ankle dorsiflexion is common after lower limb injury. The aim of this pilot study was to investigate the effect of passive ankle joint mobilization and calf muscle massage on ankle dorsiflexion range of motion in adults with residual restricted dorsiflexion. The secondary aim was to assess the methodology of the pilot study to inform a larger clinical trial. METHOD: The study design was a randomized crossover trial with assessor blinding. Twenty-five healthy participants with a history of lower limb injury were included in the study. Ankle joint mobilization and calf muscle massage were applied for 5 min in a random order, one to two weeks apart. Ankle dorsiflexion was measured by using the weight-bearing lunge pre- and post-intervention (cm). Paired t-tests were used to analyze the effect of the manual therapy interventions on restricted ankles. A minimal detectable difference 95% (MMD95) was calculated. The pilot study was analyzed for suitability of inclusion criteria, blinding of assessors and the manual therapist, and the washout period. RESULTS: A significant increase in dorsiflexion was demonstrated for ankle joint mobilization (change score = 0.51 ± 0.76, p = 0.003) and calf muscle soft tissue massage (change score = 0.91 ± 1.07, p < 0.001). There was no difference in change scores between manual therapy techniques (mobilization 0.51 ± 0.76, massage 0.91 ± 1.07, p = 0.12). Evaluation of the pilot study revealed limitations to be modified in future studies. CONCLUSION: These preliminary data indicate ankle joint mobilization and calf muscle soft tissue massage had similar effects on increasing ankle dorsiflexion range of motion in ankles with residual dorsiflexion restriction.

Increased STAT expression in Reed-Sternberg cells as a potential positive prognostication biomarker in Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) prognostication primarily relies on clinical and radiological factors. Despite this, a subset of patients still progress. Immunohistochemistry (IHC) based biomarkers on diagnostic tissue have not been routinely used for prognostication. A multicentre retrospective analysis identified 62 patients with cHL. IHC on diagnostic tissues was used to stain Reed-Sternberg cells (RS) cells for STAT1, pSTAT3, p53 and tumour microenvironment for CD68 and PD-1. IHC stains were scored by anatomical pathologists blinded to patients and their outcomes and correlated with survival. Strong intensity of STAT1 and pSTAT3 staining correlated with improved overall survival (OS), with hazard ratios (HR) of 0.21 [95% confidence interval (CI) 0.06-0.76] and 0.22 (95% CI 0.06-0.84), respectively. Similarly, the median OS for weak versus strong STAT1 or pSTAT3 staining was 8.8 years versus not reached. Other IHC stains did not correlate with prognosis. In this cohort of cHL patients, downregulation of immunohistochemical STAT1 or pSTAT3 in RS cells is associated with inferior OS, suggesting STAT transcription within the pathognomonic RS cells may have tumour suppressor function and may be a potential biomarker for cHL prognosis.

Peritesticular scarring: An unusual presentation of hemophilia B.

Hemophilia is an inherited clotting disorder that typically presents as spontaneous hemorrhage or prolonged, excessive bleeding following minor trauma. Abnormalities of the genitourinary tract are a rare manifestation of the disease. Here, we report a case of undiagnosed hemophilia B in a teenage boy presenting with worsening testicular pain and a dumbbell-shaped testis. Scrotal ultrasound identified the presence of a hypoechogenic band constricting the left testicle. Surgical exploration of the left testis was performed with release and sampling of the fibrous tunica vaginalis tissue responsible for the testicular deformity. Histopathological analysis revealed evidence of chronic interstitial inflammation with hypocellular keloid-like fiber formation suggestive of old hemorrhage. The procedure was complicated by a delayed scrotal hematoma. Coagulation studies confirmed a prolonged activated partial thromboplastin time and factor IX assay of 5%. Scrotal evacuation with the administration of intraoperative tranexamic acid achieved effective hemostasis. The patient is doing well with ongoing hematology review and prophylactic recombinant factor IX administration.

Noninvasive Assessment of Acute Graft-Versus-Host Disease of the Gastrointestinal Tract After Allogeneic Hemopoietic Stem Cell Transplantation Using 18F-FDG PET.

Acute graft-versus-host disease of the gastrointestinal tract (acute GIT-GVHD) often complicates allogeneic hemopoietic stem cell transplantation (AHSCT). 18F-FDG PET/CT is known to detect active inflammation and may be a useful noninvasive test for acute GIT-GVHD. The objective of this study was to evaluate the diagnostic utility of 18F-FDG PET/CT to noninvasively assess patients with clinically suspected acute GIT-GVHD. Fifty-one AHSCT patients with clinically suspected acute GIT-GVHD prospectively underwent 18F-FDG PET/CT scanning followed by upper and lower GIT endoscopy within 7 d. Endoscopic biopsies of 4 upper GIT and 4 colonic segments were obtained for histology to compare with corresponding quantitative segmental 18F-FDG PET/CT SUVmax Receiver-operating-characteristic curve (ROC) analysis was performed to determine predictive capacity of 18F-FDG PET/CT SUVmax for acute GIT-GVHD. A separate qualitative visual 18F-FDG PET/CT analysis was also performed for comparison. Results: Twenty-three of 51 (45.1%) patients had biopsy-confirmed acute GIT-GVHD, with 19 of 23 (82.6%) having upper GIT and 22 of 22 (100%) colonic involvement. One of 23 patients did not undergo a colonoscopy. GVHD involved the entire colon contiguously in 21 of 22 patients. For quantitative analysis, histology from 4 upper GIT and 4 colonic segments were compared with 18F-FDG PET/CT SUVmax Colonic segments positive for GVHD had a higher SUVmax (4.1 [95% CI, 3.6-4.5]) than did normal colonic segments (2.3 [1.9-2.7], P = 0.006). No difference was demonstrated in upper GIT segments. Quantitative 18F-FDG PET/CT yielded a 69% sensitivity, 57% specificity, 73% negative predictive value, and 59% positive predictive value for the detection of GVHD compared with 70%, 76%, 76%, and 68%, respectively, for qualitative analysis. Conclusion: 18F-FDG PET is a useful noninvasive diagnostic test for acute GIT-GVHD, which when present always involves the colon and usually in its entirety, suggesting colonic biopsy obtained by sigmoidoscopy is adequate for histologic confirmation when acute GIT-GVHD is suspected. Of note, 18F-FDG PET cannot distinguish acute GIT-GVHD from non-GVHD inflammatory changes in the colon.

Oncological outcomes after piecemeal endoscopic mucosal resection of large non-pedunculated colorectal polyps with covert submucosal invasive cancer.

OBJECTIVE: Management of covert submucosal invasive cancer (SMIC) discovered after piecemeal endoscopic mucosal resection (pEMR) of large (>20 mm) non-pedunculated colorectal polyps is challenging. The residual cancer risk is largely unknown. We sought to evaluate this in a large tertiary referral cohort. DESIGN: Cases of covert SMIC following pEMR were identified and followed. Oncological outcomes after surgery were divided based on residual intramural cancer, lymph node metastases (LNM) or both. Risk factors for residual intramural cancer and LNM were analysed based on the original pEMR histological variables. Risk parameters were analysed with respect to low and high-risk variables for residual intramural cancer and LNM. RESULTS: Among 3372 cases of large non-pedunculated colorectal polyps, 143 cases of covert SMIC (4.2%) were identified. 109 underwent surgical resection. Histological analysis of pEMR histology was available in 98 of 109 (90%) cases. 62 cases (63%) had no residual malignancy. 36 cases had residual malignancy (residual intramural cancer n=24; LNM n=5; both n=7). All cases of residual intramural cancer could be identified by a R1 histological deep margin. Cases with poor differentiation (PD) and/or lymphovascular invasion (LVI) had a high risk of LNM (12/33), with a very low risk without these criteria (<1%; 0/65). Cases at low risk for LNM with R0 deep margin have a low risk of residual intramural cancer (<1%; 0/35). CONCLUSION: The majority of cases of large non-pedunculated colorectal polyps with covert SMIC following pEMR will have no residual malignancy. The risk of residual malignancy can be ascertained from three key variables: PD, LVI and R1 deep margin.

Accuracy of Gastrointestinal Ultrasound and Calprotectin in the Assessment of Inflammation and its Location in Patients with an Ileoanal Pouch.

BACKGROUND AND AIMS: In symptomatic patients with ileoanal pouches, pouchoscopy is needed for accurate diagnosis but is invasive. We aimed to assess the utility of non-invasive gastrointestinal ultrasound and faecal calprotectin in ileoanal pouch patients. METHODS: Patients with an ileoanal pouch were consecutively enrolled in this cross-sectional study from clinics in Victoria, Australia. The pouchitis disease activity index was used as a reference standard. Video-recorded pouchoscopies were reviewed by three gastroenterologists. Pouch, pre-pouch, and cuff biopsies were reviewed by a single pathologist. Ultrasound was performed by a single gastroenterologist transabdominally and transperineally. Faecal calprotectin was measured from morning stool samples. All examiners were blinded to patients' clinical history. RESULTS: A total of 44 participants had a pouchoscopy, of whom 43 had a faecal calprotectin test and 42 had an ultrasound; 17 had pouchitis, 15 had pre-pouch ileitis, and 16 had cuffitis. Pouch wall thickness of <3 mm was 88% sensitive in excluding pouchitis, and pouch wall thickness of ≥4 mm was 87% specific in diagnosing pouchitis. Transabdominal ultrasound had good utility [area under the curve: 0.78] in diagnosing moderate-severe pre-pouch ileitis. Transperineal ultrasound had good utility for the diagnosis of pouchitis [area under the curve: 0.79]. Faecal calprotectin differentiated inflammatory from non-inflammatory pouch disorders, such as irritable pouch syndrome, with an area under the curve of 0.90. Faecal calprotectin <100 µg/g ruled out inflammatory pouch disorders with a sensitivity of 94%. CONCLUSIONS: Faecal calprotectin and ultrasound are accurate and complementary tests to diagnose and localise inflammation of the ileoanal pouch. Prospective studies are needed to validate proposed sonographic indices and calprotectin levels.

The Reliability and Accuracy of Endoscopic Items and Scores Used in the Assessment of the Ileoanal Pouch and Cuff.

BACKGROUND AND AIMS: Currently used endoscopic items for the assessment of pouchitis and cuffitis have deficiencies in reliability and validation. We assessed the reliability and accuracy of new endoscopic items for pouchitis and of the Ulcerative Colitis Endoscopic Index of Severity [UCEIS] for cuffitis. METHODS: Three new endoscopic items were assessed and included in the Monash pouchitis endoscopic subscore: bleeding [absent/contact/spontaneous]; erosions [absent/<10/≥10]; and ulceration [absent/<10%/≥10%]. Three raters evaluated 44 pouchoscopy videos in duplicates, in random order. Intra- and inter-rater reliability of all endoscopic items and UCEIS were assessed. Clinical and histological pouchitis disease activity index [PDAI] subscores were also assessed and faecal calprotectin was measured. RESULTS: All three Monash endoscopic items had substantial intra-rater reliability with intraclass correlation coefficients [ICCs] >0.61 [95% CI >0.61], compared with only ulcers from the currently used PDAI endoscopic subscore, but inter-rater reliability was only substantial for ulceration and no better than those of the currently used endoscopic items. The Monash endoscopic subscore had a strong positive correlation with the reference standard global endoscopic lesion severity r = 0.80 [95% CI 0.80-0.80] and the reference standard PDAI endoscopic subscore r = 0.70 [95% CI 0.67-0.73], which was higher than the correlation observed for the currently used PDAI endoscopic subscore. The UCEIS had substantial intra-rater reliability, but only fair inter-rater reliability and poor diagnostic performance for cuffitis. CONCLUSIONS: The Monash endoscopic items, and endoscopic subscore they generate, have enhanced overall performance compared with the currently used PDAI items and subscore. Further validation and responsiveness to change in disease state are indicated.

Continuous Diffusion of Oxygen Adjunct Therapy to Improve Scar Reduction After Cervicotomy - A Proof of Concept Randomized Controlled Trial.

BACKGROUND: Dressing materials are known to influence post-operative surgical wound healing and scar formation (SF). A particular dressing that could promote wound hydration is essential to ensure quick epithelialization and reduce SF. This study examined the effectiveness of a novel Continuous Diffusion of Oxygen (CDO) dressing to reduce scar length post cervicotomy. METHODS: A randomized controlled trial was performed in patients undergoing cervicotomy, either for thyroid or parathyroid disease. Patients were randomized to either control (CG) or intervention (IG) groups. The IG received a portable CDO system (TransCu O2, EO2 Concepts Inc., TX, USA), whereas the CG received a standard dressing for a 4-week period. The primary outcome was >10% of scar length reduction and %change in scar length. RESULTS: 21 patients were recruited (Age: 53 ± 16 years; 90% female; CG = 9, IG = 12). 5 patients were lost to follow-up. At 4 weeks, 88.8% of the IG significantly achieved >10% of scar reduction (versus CG = 28.5%, d = 0.48, P = 0.049), showing a 40.4% smaller scar (15.7% versus 11.2%, d = 0.13, P = 0.72) compared to the CG. However, the difference was not significant. A sub-sample of patients undergoing thyroidectomy showed a significant scar reduction using CDO (IG = 11.6% versus CG = 5.1%, d = 2.96, P = 0.009). CONCLUSIONS: This is the first study to assess scar reduction using CDO adjunct therapy after cervicotomy. Advanced CDO dressings may assist wound healing showing improved outcomes for scar visualization in patients undergoing thyroidectomy. A larger sample is required to validate this observation.

The impact of incomplete clinical information and initial biopsy technique on the histopathological diagnosis of cutaneous melanoma.

BACKGROUND/OBJECTIVES: Increased rates of histopathological misdiagnosis of melanoma have been associated with incisional punch more so than shave biopsy when compared with complete excisional biopsy. It is unknown how the increasing utilisation of shave biopsy may impact melanoma diagnosis. The extent to which the provision of clinical information to the pathologist may improve diagnostic accuracy remains unclear. This study assessed the impact of both initial biopsy technique and provision of adequate clinical information to pathologists on the accuracy of histopathological diagnosis of melanoma and disease progression. METHODS: We conducted a retrospective cohort with nested case-control study of all histopathological false-negative and false-positive melanoma diagnoses from January 2014 to May 2019 from the Victorian Melanoma Service electronic database. Cases were assessed for the initial biopsy type, provision of clinical information on pathology request forms and disease progression associated with false-negative diagnosis. RESULTS: Partial shave biopsy had higher odds of false-negative (OR 5.19, 95% CI 2.89-9.32; P < 0.001) and false-positive diagnoses (OR 1.95, 95% CI 1.45-2.63; P < 0.001) of melanoma when compared with elliptical excisional biopsy. These odds ratios were comparable with those found with incisional punch biopsy. Providing the suspected clinical diagnosis to pathologists also reduced the odds of false-negative diagnosis with melanoma progression by 3.8-fold (P = 0.02). CONCLUSION: The choice of initial biopsy technique and providing the suspected clinical diagnosis to pathologists are important for correct histopathological diagnosis of cutaneous melanoma and prevention of further disease progression.

Effect of Workstation Type on the Relationship Between Fatigue, Physical Activity, Stress, and Sleep.

OBJECTIVE: This study examined office workstation types' impact on the relationship between fatigue and three health metrics: physical activity, stress, and sleep quality. METHODS: Data from 225 office workers were collected for perceived fatigue, perceived sleep quality (Pittsburgh Sleep Quality Index [PSQI]), physiological stress response (standard deviation of heart rate variability [HRV]), and physical activity (total activity in minutes) during three consecutive workdays. Stress and physical activity were measured using chest-worn sensors. Workers were then categorized as tired or not-tired based on the median of the fatigue rating. RESULTS: Among tired workers, open-bench seating workers had increased physical activity, improved sleep quality, and reduced stress compared with workers in private offices and cubicles. CONCLUSIONS: Office workstation types influence physical activity and levels of stress during work hours, which in turn affect sleep quality.

Successful treatment of HIV-associated lupus-like glomerulonephritis with mycophenolic acid.

HIV-associated lupus-like glomerulonephritis is an uncommon but well-described entity. Treatment has traditionally focused on control of HIV viremia with some using adjuvant steroids. Mycophenolic acid may prove to be a novel, nonsteroid, therapy in patients with active glomerulonephritis despite control of the underlying infection.

Safe administration of anti-PD-1 immunotherapy in a patient with pre-existing primary biliary cholangitis.

A 63-year-old female presented with cholestatic liver function tests in November 2016. Screening tests were negative for other causes and liver biopsy revealed primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) overlap. Ursodeoxycholic acid and azathioprine was initiated. In September 2018 she was diagnosed with Stage III BRAF wild-type melanoma. Azathioprine was ceased and adjuvant immunotherapy was not recommended due to the risk of worsening PBC/AIH. Surveillance PET revealed metastatic disease and she commenced pembrolizumab. Restaging PET after 4 cycles showed a complete metabolic response, with no hepatitis or other significant toxicity. We believe this is the first reported case of the safe administration of pembrolizumab in a patient with known PBC/AIH. Treatment duration in such high risk patients needs further investigation.

Insulinoma presenting with post-prandial hypoglycaemia following fundoplication.

Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an uncommon and challenging case of insulinoma soon after upper gastrointestinal surgery. A 63-year-old man presented with 6 months of post-prandial hypoglycaemia beginning after a laparoscopic revision of Toupet fundoplication. Hyperinsulinaemic hypoglycaemia was confirmed during a spontaneous episode and in a mixed-meal test. Localisation studies including magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and gallium dotatate positron emission tomography (68Ga Dotatate PET) were consistent with a small insulinoma in the mid-body of the pancreas. The lesion was excised and histopathology was confirmed a localised well-differentiated neuroendocrine pancreatic neoplasm. There have been no significant episodes of hypoglycaemia since. This case highlights several key points. Insulinoma should be sought in proven post-prandial hyperinsulinaemic hypoglycaemia - even in the absence of fasting hypoglycaemia. The use of nuclear imaging targeting somatostatin and GLP1 receptors has improved accuracy of localisation. Despite these advances, accurate surgical resection can remain challenging. LEARNING POINTS: Hypoglycaemia is defined by Whipple's triad and can be provoked by fasting or mixed-meal tests.Although uncommon, insulinomas can present with post-prandial hypoglycaemia.In hypoglycaemia following gastrointestinal surgery (i.e. bariatric surgery or less commonly Nissen fundoplication) dumping syndrome or non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) should be considered.Improved imaging techniques including MRI, endoscopic ultrasound and functional nuclear medicine scans aid localisation of insulinomas.Despite advances in imaging and surgical techniques, accurate resection of insulinomas remains challenging.

Neutrophil macroaggregates promote widespread pulmonary thrombosis after gut ischemia.

Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging.

Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.

The effect of ambient lighting on Laser Doppler Imaging of a standardized cutaneous injury model.

OBJECTIVE: The aim of this study was to investigate the potential confounding effects of four different types of ambient lighting on the results of Laser Doppler Imaging (LDI) of a standardized cutaneous injury model. METHODS: After applying a mechanical stimulus to the anterior forearm of a healthy volunteer and inducing a wheal and arteriolar flare (the Triple response), we used a Laser Doppler Line Scanner (LDLS) to image the forearm under four different types of ambient lighting: light-emitting-diode (LED), compact fluorescent lighting (CFL), halogen, daylight, and darkness as a control. A spectrometer was used to measure the intensity of light energy at 785 nm, the wavelength used by the scanner for measurement under each type of ambient lighting. RESULTS: Neither the LED nor CFL bulbs emitted detectable light energy at a wavelength of 785 nm. The color-based representation of arbitrary perfusion unit (APU) values of the Triple response measured by the scanner was similar between darkness, LED, and CFL light. Daylight emitted 2 mW at 785 nm, with a slight variation tending more towards lower APU values compared to darkness. Halogen lighting emitted 6 mW of light energy at 785 nm rendering the color-based representation impossible to interpret. CONCLUSIONS: Halogen lighting and daylight have the potential to confound results of LDI of cutaneous injuries whereas LED and CFL lighting did not. Any potential sources of daylight should be reduced and halogen lighting completely covered or turned off prior to wound imaging.

Isavuconazole as salvage therapy for mucormycosis.

Mucormycosis carries a high mortality rate with few therapeutic options available. We describe a man with pulmonary/splenic mucormycosis complicating hypoplastic myelodysplastic syndrome on a background of chronic kidney disease, who achieved a complete response with salvage isavuconazole therapy following intolerance of consecutive courses of liposomal amphotericin and posaconazole therapy.