Validated machine learning tools to distinguish immune checkpoint inhibitor, radiotherapy, COVID-19 and other infective pneumonitis.

BACKGROUND: Pneumonitis is a well-described, potentially disabling, or fatal adverse effect associated with both immune checkpoint inhibitors (ICI) and thoracic radiotherapy. Accurate differentiation between checkpoint inhibitor pneumonitis (CIP) radiation pneumonitis (RP), and infective pneumonitis (IP) is crucial for swift, appropriate, and tailored management to achieve optimal patient outcomes. However, correct diagnosis is often challenging, owing to overlapping clinical presentations and radiological patterns. METHODS: In this multi-centre study of 455 patients, we used machine learning with radiomic features extracted from chest CT imaging to develop and validate five models to distinguish CIP and RP from COVID-19, non-COVID-19 infective pneumonitis, and each other. Model performance was compared to that of two radiologists. RESULTS: Models to distinguish RP from COVID-19, CIP from COVID-19 and CIP from non-COVID-19 IP out-performed radiologists (test set AUCs of 0.92 vs 0.8 and 0.8; 0.68 vs 0.43 and 0.4; 0.71 vs 0.55 and 0.63 respectively). Models to distinguish RP from non-COVID-19 IP and CIP from RP were not superior to radiologists but demonstrated modest performance, with test set AUCs of 0.81 and 0.8 respectively. The CIP vs RP model performed less well on patients with prior exposure to both ICI and radiotherapy (AUC 0.54), though the radiologists also had difficulty distinguishing this test cohort (AUC values 0.6 and 0.6). CONCLUSION: Our results demonstrate the potential utility of such tools as a second or concurrent reader to support oncologists, radiologists, and chest physicians in cases of diagnostic uncertainty. Further research is required for patients with exposure to both ICI and thoracic radiotherapy.

A Novel Radiogenomics Biomarker for Predicting Treatment Response and Pneumotoxicity From Programmed Cell Death Protein or Ligand-1 Inhibition Immunotherapy in NSCLC.

INTRODUCTION: Patient selection for checkpoint inhibitor immunotherapy is currently guided by programmed death-ligand 1 (PD-L1) expression obtained from immunohistochemical staining of tumor tissue samples. This approach is susceptible to limitations resulting from the dynamic and heterogeneous nature of cancer cells and the invasiveness of the tissue sampling procedure. To address these challenges, we developed a novel computed tomography (CT) radiomic-based signature for predicting disease response in patients with NSCLC undergoing programmed cell death protein 1 (PD-1) or PD-L1 checkpoint inhibitor immunotherapy. METHODS: This retrospective study comprises a total of 194 patients with suitable CT scans out of 340. Using the radiomic features computed from segmented tumors on a discovery set of 85 contrast-enhanced chest CTs of patients diagnosed with having NSCLC and their CD274 count, RNA expression of the protein-encoding gene for PD-L1, as the response vector, we developed a composite radiomic signature, lung cancer immunotherapy-radiomics prediction vector (LCI-RPV). This was validated in two independent testing cohorts of 66 and 43 patients with NSCLC treated with PD-1 or PD-L1 inhibition immunotherapy, respectively. RESULTS: LCI-RPV predicted PD-L1 positivity in both NSCLC testing cohorts (area under the curve [AUC] = 0.70, 95% confidence interval [CI]: 0.57-0.84 and AUC = 0.70, 95% CI: 0.46-0.94). In one cohort, it also demonstrated good prediction of cases with high PD-L1 expression exceeding key treatment thresholds (>50%: AUC = 0.72, 95% CI: 0.59-0.85 and >90%: AUC = 0.66, 95% CI: 0.45-0.88), the tumor's objective response to treatment at 3 months (AUC = 0.68, 95% CI: 0.52-0.85), and pneumonitis occurrence (AUC = 0.64, 95% CI: 0.48-0.80). LCI-RPV achieved statistically significant stratification of the patients into a high- and low-risk survival group (hazard ratio = 2.26, 95% CI: 1.21-4.24, p = 0.011 and hazard ratio = 2.45, 95% CI: 1.07-5.65, p = 0.035). CONCLUSIONS: A CT radiomics-based signature developed from response vector CD274 can aid in evaluating patients' suitability for PD-1 or PD-L1 checkpoint inhibitor immunotherapy in NSCLC.

A radiomics-based decision support tool improves lung cancer diagnosis in combination with the Herder score in large lung nodules.

BACKGROUND: Large lung nodules (≥15 mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk. METHODS: 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores. FINDINGS: 499 patients had technically evaluable scans (mean age 69 ± 11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77-0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70-0.81], DeLong p = 0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80-0.93) compared to 0.67 (95% CI 0.55-0.76, DeLong p = 0.002) for the Brock score and 0.83 (95% CI 0.75-0.90, DeLong p = 0.4) for the Herder score. In the international external test set (n = 151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63-0.85). 18 out of 22 (82%) malignant nodules in the Herder 10-70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention. INTERPRETATION: The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models. FUNDING: This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316).

A 4-year study of the use of the short metacarpal cast in the management of metacarpal shaft fractures.

We report on our experience of using a short, moulded metacarpal cast over a 4-year period in the non-surgical management of metacarpal shaft fractures. Between 6 April 2015 and 6 April 2019, 117 patients were treated using this method. The majority were male, and the mean age was 24.6 years. The most common mechanism of injury was a punch injury (73 patients, 62%). Fifteen patients (13%) were treated for multiple metacarpal fractures. Immediately after cast removal, 68% had a full range of finger movement and 68% were pain free. Few required formal hand therapy. Fifteen patients experienced minor complications, primarily soft tissue irritation from the cast and non-limiting extensor lag. The moulded short metacarpal cast is an effective non-surgical treatment for angulated extra-articular metacarpal fractures of the diaphysis and diametaphyseal junction.Level of evidence: IV.

Surgery versus cast immobilisation for adults with a bicortical fracture of the scaphoid waist (SWIFFT): a pragmatic, multicentre, open-label, randomised superiority trial.

BACKGROUND: Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less. METHODS: This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs. An independent remote randomisation service used a computer-generated allocation sequence with randomly varying block sizes to randomly assign participants (1:1) to receive either early surgical fixation (surgery group) or below-elbow cast immobilisation followed by immediate fixation if non-union of the fracture was confirmed (cast immobilisation group). Randomisation was stratified by whether or not there was displacement of either a step or a gap of 1-2 mm inclusive on any radiographic view. The primary outcome was the total patient-rated wrist evaluation (PRWE) score at 52 weeks after randomisation, and it was analysed on an available case intention-to-treat basis. This trial is registered with the ISRCTN registry, ISRCTN67901257, and is no longer recruiting, but long-term follow-up is ongoing. FINDINGS: Between July 23, 2013, and July 26, 2016, 439 (42%) of 1047 assessed patients (mean age 33 years; 363 [83%] men) were randomly assigned to the surgery group (n=219) or to the cast immobilisation group (n=220). Of these, 408 (93%) participants were included in the primary analysis (203 participants in the surgery group and 205 participants in the cast immobilisation group). 16 participants in the surgery group and 15 participants in the cast immobilisation group were excluded because of either withdrawal, no response, or no follow-up data at 6, 12, 26, or 52 weeks. There was no significant difference in mean PRWE scores at 52 weeks between the surgery group (adjusted mean 11·9 [95% CI 9·2-14·5]) and the cast immobilisation group (14·0 [11·3 to 16·6]; adjusted mean difference -2·1 [95% CI -5·8 to 1·6], p=0·27). More participants in the surgery group (31 [14%] of 219 participants) had a potentially serious complication from surgery than in the cast immobilisation group (three [1%] of 220 participants), but fewer participants in the surgery group (five [2%]) had cast-related complications than in the cast immobilisation group (40 [18%]). The number of participants who had a medical complication was similar between the two groups (four [2%] in the surgery group and five [2%] in the cast immobilisation group). INTERPRETATION: Adult patients with scaphoid waist fractures displaced by 2 mm or less should have initial cast immobilisation, and any suspected non-unions should be confirmed and immediately fixed with surgery. This treatment strategy will help to avoid the risks of surgery and mostly limit the use of surgery to fixing fractures that fail to unite. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Rare and unusual clinicopathologic presentation of renal AL amyloidosis.

Rarely, renal light chain (AL) amyloidosis may present without significant proteinuria owing to glomerular sparing and amyloid deposition confined to the vasculature and tubulointerstitium.

Ulna Nerve Decompression at the Elbow in Patients with Normal Nerve Conduction Tests.

BACKGROUND: Ulna nerve compression at the elbow is the second most common neuropathy of the upper limb. It has been suggested that nerve conduction tests are required to correctly make the diagnosis. The aim of this study was to assess whether patients with normal nerve conduction testing benefitted from surgical release of the ulna nerve. METHODS: 56 patients with symptoms of ulna nerve compression at the elbow were evaluated prospectively. All patients underwent electrophysiology testing followed by ulna nerve decompression irrespective of the results of the electrophysiology testing. Functional scores using the QuickDASH and PEM score were collected up to 12 months post-surgery. RESULTS: No difference was found between the group with normal and the group with abnormal electrophysiology studies. CONCLUSIONS: We conclude that patients who clinically have ulna nerve compression still benefit from ulna nerve decompression despite normal nerve conduction tests.

Review of treatment of acute scaphoid fractures: R1.

Scaphoid fractures are common. Clinical suspicion and early diagnosis and treatment are vital in order to avoid complications such as avascular necrosis. The management of these fractures depends on fracture characteristics, specifically the degree of displacement. With consideration of patient factors, such as occupation, the treatment can be non-operative or operative. There has been much debate in the recent literature regarding the best management of these fractures. The purpose of this review was to identify the current evidence for non-operative and operative treatment. Undisplaced and minimally displaced fractures can be managed non-operatively with a scaphoid cast. Surgical treatment is used for fractures with displacement of >1 mm.

In vitro and in vivo characterisation of a novel c-FLIP-targeted antisense phosphorothioate oligonucleotide.

Previous studies have suggested that the caspase 8 inhibitor FLIP is a promising anti-cancer therapeutic target. In this study, we characterised a novel FLIP-targeted antisense phosphorothioate oligonucleotide (AS PTO). FLIP AS and control PTOs were assessed in vitro in transient transfection experiments and in vivo using xenograft models in Balb/c nude mice. FLIP expression was assessed by QPCR and Western. Apoptosis induction was determined by flow cytometry and Western. Of 5 sequences generated, one potently down-regulated FLIP. AS PTO-mediated down-regulation of FLIP resulted in caspase 8 activation and apoptosis induction in non-small cell lung (NSCLC) cells but not in normal lung cells. Similar results were observed in colorectal and prostate cancer cells. Furthermore, the FLIP AS PTO sensitized cancer cells but not normal lung cells to apoptosis induced by rTRAIL. Moreover, the FLIP AS PTO enhanced chemotherapy-induced apoptosis in NSCLC cells. Importantly, compared to a control non-targeted PTO, intra-peritoneal delivery of FLIP AS PTO inhibited the growth of NSCLC xenografts and enhanced the in vivo antitumour effects of cisplatin. We have identified a novel FLIP-targeted AS PTO that has in vitro and in vivo activity and which therefore has potential for further pre-clinical development.

Direct anterior neck skin excision for cervicomental laxity.

BACKGROUND: Skin and platysma muscle laxity in the cervicomental area is a surgical challenge. Several approaches are possible, including an extended facelift, platysmaplasty, and liposuction. Severe cases are difficult to treat, and a direct approach might sometimes be indicated. The aim of this study was to evaluate the outcomes and clarify the indications for a direct approach with anterior neck skin excision. METHODS: Patients undergoing anterior neck skin excision were recruited retrospectively and prospectively. Subjective and objective assessments by the patients and their surgeon were made pre- and postoperatively. Cervicomental skin is excised with a Z-plasty to leave the horizontal limb hidden in the cervicomental angle. This is a local anaesthetic office procedure. RESULTS: Surgery was performed on 17 patients in our unit over a 10-year period. Indications included patient choice, expense, unsuitability for general anaesthesia, and previous failure of facelift procedures. Ellenbogen-Karlin scoring criteria for the cervicomental angle showed a mean improvement from 0.6 to 3.3 points out of 5. There were no wound infections or flap necroses and no revisional surgery was required. Three patients underwent steroid injections for scar hypertrophy. CONCLUSION: The procedure is simple, quick, safe, and effective at restoring the cervicomental angle but leaves a potentially very problematic scar.

Comparison of fibrin glue with sutures for pterygium excision surgery with conjunctival autografts.

PURPOSE: To compare pterygium excision conjunctival autograft surgery using Tisseel fibrin glue versus Vicryl sutures. METHOD: Prospective randomized clinical trial. Fifty patients were randomized into either sutured graft or glued graft groups. Twenty-five received standard conjunctival autograft sutured with Vicryl and 25 received surgery with the autograft placed with Tisseel fibrin glue. Outcome measures include surgical time, patient discomfort, pathology, complications and recurrence rates at 3, 6 and 12 months. Patients were followed up at days 1, 7, 14, 30, 90, 180 and 365. RESULTS: The mean surgical time for the glue group was significantly shorter at 12 min compared with the suture group at 26 min (P < 0.001). Postoperative pain was significantly less at day 1 (P < 0.001) and day 2 (P < 0.05) but was not significantly different following these visits. Complications in the glue group included one patient with an absent graft at week 1 that required revision of the graft. At 3 months there were no recurrences in the glue group and two recurrences in the suture group. The 6- and 12-month recurrence rate was unchanged and not significantly different between the glue and suture groups (both 0/24 and 2/23, respectively). CONCLUSION: Both glued and sutured conjunctival autografting procedures are safe and effective methods for pterygium surgery. The glued autograft recurrence rate at 12 months was similar to that of sutured grafts. Conjunctival autograft with fibrin glue in pterygium surgery decreased surgical time and resulted in less postoperative pain in the first 48 hours but had a higher complication rate.

Hand knife versus powered dermatome: current opinions, practices, and evidence.

Some surgeons prefer to use powered dermatomes when harvesting split-thickness skin grafts, while others prefer the hand knife. We conducted a postal survey of British plastic surgery units, contacted medicolegal departments, and investigated the literature to explore the reasoning for any preferences and the existing evidence to support such practices. Two hundred thirty-eight surgeons from 30 units replied, 145 (61%) preferring to use the powered dermatome, primarily as they believed it provided for better-quality graft and donor sites. Ninety-five (40%) respondents felt they were potentially open to successful litigation by using a hand knife when a powered dermatome was available. We found no evidence to support such clinical or medicolegal views and conclude that numerous misconceptions exist about skin-graft harvesting instruments. We suggest that surgeons should use whichever instrument they feel will, in their hands, provide the optimum result and not be directed by unfounded opinions.