Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer.

Purpose: Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data link cigarette smoke as a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming the cellular reductive state. Experimental design: Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology. Results: Cigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of HPV status. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates both expression of PDL1 and the secretory phenotype of HNSCC cells through activation of NF-κB resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and altered PBMC differentiation that includes downregulated expression of antigen presentation and costimulatory genes in myeloid cells. Conclusion: Cigarette smoke exposome is a potent activator of the Nrf2 pathway and is a likely primary trigger for the tripartite phenotype of aggressive HNSCC consisting of: 1) reduced chemotherapy sensitivity, 2) enhanced metastatic potential and 3) suppressed anti-tumor immunity. Statement of significance: The smoke exposome drives aggressive tumor behavior, treatment resistance and suppressed immunity through coordinated metabolic reprogramming. Successfully targeting this adaptation is critical to improving survival in smokers with head and neck cancer.

Risk profiles and incidence of cardiovascular events across different cancer types.

BACKGROUND: Cancer survivors are at increased risk for cardiovascular (CV) disease, although additional data are needed to better understand the incidence of CV events across different malignancies. This study sought to characterize the incidence of major adverse CV events [myocardial infarction, stroke, unstable angina (MACE), or heart failure (HF)] across multiple cancer types after cancer diagnosis. PATIENTS AND METHODS: Patients were identified from a USA-based administrative claims database who had index cancer diagnoses of breast, lung, prostate, melanoma, myeloma, kidney, colorectal, leukemia, or lymphoma between 2011 and 2019, with continuous enrollment for ≥12 months before diagnosis. Baseline CV risk factors and incidence rates of CV events post-index were identified for each cancer. Multivariable Cox hazards models assessed the cumulative incidence of MACE, accounting for baseline risk factors. RESULTS: Among 839 934 patients across nine cancer types, CV risk factors were prevalent. The cumulative incidence of MACE was highest in lung cancer and myeloma, and lowest in breast cancer, prostate cancer, and melanoma. MACE cumulative incidence for lung cancer was 26% by 4 years (2.7-fold higher relative to breast cancer). The incidence of stroke was especially pronounced in lung cancer, while HF was highest in myeloma and lung cancer. CONCLUSIONS: CV events were especially increased following certain cancer diagnoses, even after accounting for baseline risk factors. Understanding the variable patient characteristics and associated CV events across different cancers can help target appropriate CV risk factor modification and develop strategies to minimize adverse CV events and improve patient outcomes.

The Implementation of a Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Program at a Level 1 New England Trauma Center: Feasibility and Early Outcomes.

OBJECTIVES: We evaluated the feasibility of implementing a Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) program at our urban level 1 trauma center and evaluated early outcomes. DESIGN: A multidisciplinary committee including physicians (trauma surgery, emergency medicine, vascular surgery, and interventional radiology) and nurses created clinical practice guidelines for the placement of REBOA at our institution. All trauma surgeons and critical care board certified emergency medicine physicians were trained in placement and nurses received management training. A formal review process was implemented to identify areas for improvement. Finally, we instituted refresher training to maintain REBOA competency. Trauma patients with noncompressible torso hemorrhage from blunt or penetrating injuries who were partial or nonresponders to blood product resuscitation were included. Pregnant patients, children, or patients with significant hemothorax or suspected aortic or cardiac injury were excluded. RESULTS: Over seven months, eight catheters were successfully placed, all on the first attempt, including six in Zone 3 and two in Zone 1. All Zone 3 catheters were placed for pelvic fracture-related bleeding which were subsequently embolized. The Zone 1 catheters were placed immediately preoperatively for intraabdominal bleeding. Upon committee review, one critique was made regarding zone selection. One patient developed an arteriovenous fistula after placement which resolved without intervention. There were no other complications and all patients survived to discharge. CONCLUSIONS: An REBOA program is feasible and safe following a comprehensive multidisciplinary effort. The efforts described here can be utilized by similar trauma programs for adaptation of this endovascular approach to bleeding control.

Clinical variation in the treatment of trigger finger: An international survey of orthopaedic and plastic surgeons.

Trigger finger is a common condition affecting the hand. Therapeutic variability surrounds the management of trigger finger, especially in the mild cases. The aim of this study was to survey secondary care surgeons to describe the current management of trigger fingers. The steering group developed a survey for hand surgeons. Following piloting, the survey was distributed to hand surgeons in the United Kingdom and The Netherlands. A total of 713 plastic surgeons and orthopaedic surgeons were invited to participate in the online survey and 440 (62%) surgeons completed the survey. In both mild and moderate cases of trigger finger, steroid injection was the preferred treatment option. Open surgery was the treatment of choice for severe cases. However, there was variation in delivery of care, including type and dosage of steroid, site of injection, interval between injections, maximum number of injections, type of incision and treatment of patients with diabetes or rheumatoid arthritis. This highlights the need for a better evidence base for the treatment of trigger fingers.

Efficacy and safety of high versus standard dose ibuprofen for patent ductus arteriosus treatment in preterm infants: A systematic review and meta-analysis.

BACKGROUND: Several small randomized controlled trials (RCTs) and observational studies have compared high (15-20/7.5-10/7.5-10 mg/kg/dose) versus standard dose (10/5/5 mg/kg/dose) ibuprofen for patent ductus arteriosus (PDA) closure, with limited evidence on efficacy and safety. OBJECTIVE: To systematically review and meta-analyze studies of high versus standard dose ibuprofen for the closure of PDA in preterm infants. METHODS: Databases were searched for RCTs and observational studies assessing high compared to standard dose of ibuprofen for PDA closure for preterm infants until August 2021. The primary outcome was failure of PDA closure after the first course of ibuprofen. The secondary outcomes were the failure of PDA closure after a second course of ibuprofen, rates of PDA ligation, all-cause mortality prior to hospital discharge, bronchopulmonary dysplasia, necrotizing enterocolitis, bleeding disorders, oliguria, and serum creatinine after treatment. RESULTS: There were 6 studies with 369 patients (3 RCT, N = 190; 3 observational studies, N = 179). Compared to standard dose, high dose ibuprofen did not significantly decrease the failure rate of PDA closure in preterm infants after the first course (Relative risk (RR) 0.74, 95% confidence interval (CI) 0.53 -1.03, 6 studies, N = 369). High dose ibuprofen significantly decreased the rates of PDA ligation compared to standard dose (RR 0.33, 95% CI 0.16 -0.70, 5 studies, N = 309). INTERPRETATION: Based on low-grade evidence, high dose ibuprofen may more effectively reduce rates of PDA ligation compared to standard dose with no increase in adverse effects, neonatal morbidities and mortality.

A rare case of an iatrogenic superior mesenteric arteriovenous fistula following surgery for a midgut volvulus.

Superior mesenteric arteriovenous fistula is an extremely rare vascular malformation with most cases occurring following abdominal trauma or surgery. They are often asymptomatic or present with various abdominal symptoms with or without features of portal hypertension. A 30-year-old man developed fistulising of the superior mesenteric artery into the superior mesenteric vein following bowel resection surgery for an acquired midgut volvulus. Although endovascular management remains the treatment of choice in such cases due to increased morbidity of a repeat abdominal surgery, definite risks remain, such as coil migration, which happened in this case. The open surgical approach remains the only option in such instances.

Role of GeneXpertMTB/RIF in the diagnosis of cutaneous tuberculosis.

BACKGROUND: cutaneous involevemtn is an important extrapulmonary manifestation of tuberculosis. It is a paucibacillary condition and has diverse clinical presentations. Sufficient data is not available regarding role of GeneXpertMTB/RIF in cutanoues tuberculosis. METHODS: in this study, BacT/Alert3D and response to antitubercular therapy were taken as gold standard and performance of GeneXpertMTB/RIF was evaluated against it in clinically and histopathologically suspected cases of cutaneous tuberculosis. RESULTS: forty seven patients were included in the study of which commonest presentation was scrofuloderma (42.6%) followed by lupus vulgaris (40.4%). Granulomatous inflammation on histopathology was seen in 75.5% patients on skin biopsy. Sic patients had extracutaneous focus of tuberculosis. In 14 (29.79%), culture of skin biopsy was positive for M. tuberculosis and all showed complete response to ATT in 6 months. GeneXpertMTB/RIF detected M. tuberculsois in 4 samples. CONCLUSION: GeneXpertMTB/RIF is not a reliable tool for diagnosis of cutaneous tuberculosis. Clinic-histopathological correlation along with response to ATT is needed for confirmation of diagnosis of cutaneous tuberculosis.

A rare case of an iatrogenic superior mesenteric arteriovenous fistula following surgery for a midgut volvulus.

Superior mesenteric arteriovenous fistula is an extremely rare vascular malformation with most cases occurring following abdominal trauma or surgery. They are often asymptomatic or present with various abdominal symptoms with or without features of portal hypertension. A 30-year-old man developed fistulising of the superior mesenteric artery into the superior mesenteric vein following bowel resection surgery for an acquired midgut volvulus. Although endovascular management remains the treatment of choice in such cases due to increased morbidity of a repeat abdominal surgery, definite risks remain, such as coil migration, which happened in this case. The open surgical approach remains the only option in such instances.

A proposed "Radiological Evaluation Score for Bone Tumors" (REST): An objective system for assessment of a radiograph in patients with suspected bone tumor.

BACKGROUND: Although radiographs have been widely used in the evaluation of patients with suspected bone tumors, the lack of an objective radiological assessment method leads to a challenge in reaching correct diagnosis. The study aimed to propose a Radiological Evaluation Score for Bone Tumors (REST) which includes eight radiological factors [characteristics, content, cortical breach, distinctiveness, distribution, periosteal reaction, fracture, and soft tissue swelling] to form a single score along with its validation by multidisciplinary observers. METHODS: We reviewed the radiographs of 100 patients with a primary bone tumor which were selected at random from the database between January 2017 and January 2019 of a tertiary cancer center. Four reviewers (two orthopedic oncologists and two surgical oncologists) independently assessed the radiographs, based on the reporting system of REST. We constituted two groups according to the probable diagnosis of bone tumor (suspected benign tumor and suspected malignant tumor). RESULTS: The mean score in the suspected benign tumor group was 1.1 (range 0-3, 95% CI 0.8-1.3) and in malignant tumor group was 6.1 (range 2-8, 95% CI 5.8-6.4). A receiver operator characteristic (ROC) curve for REST was with a cutoff of 3.5, with the most diagnostic value area under curve (AUC) of 0.99. The sensitivity was 98% and specificity was 100% with a positive predictive value of 100% and a negative predictive value of 98%. The inter-observer correlation coefficient was 0.985 (p value < 0.05), and Fleiss kappa value for the prediction of the benign or malignant lesion was 0.97 (p value < 0.05). The characteristics and content of tumor, cortical erosion, distinctiveness, distribution, periosteal reaction, and soft tissue mass had a significant correlation with the aggressiveness of bone lesion p value < 0.05. CONCLUSIONS: The Radiological Evaluation Score for Bone Tumors (REST) is a structured reporting and objective method for the assessment of radiographs in patients with suspected bone tumors. This method is a reliable and helpful tool for clinicians in their outdoor patient department to differentiate a radiograph of a suspected benign tumor from a malignant bone tumor.

Modified vertical osteotomy cut in bilateral sagittal split osteotomy.

Bilateral sagittal split osteotomy (BSSO) is the most common orthognathic surgical procedure for the correction of facial deformities. Like any other surgical procedure, it is also associated with a risk of complications. One of these is described in the literature as notching at the lower inferior border of the mandible. Such discontinuity in the contour of the lower border is often a concern for patients. To overcome this complication, we recommend a modified vertical osteotomy cut while performing BSSO.

What is a better modality of maxillomandibular fixation: bone-supported arch bars or Erich arch bars? A systematic review and meta-analysis.

Any procedure that aims to manage maxillofacial fracture is incomplete without meticulous maxillomandibular fixation (MMF). For decades, Erich arch bars (EABs) have been used for this purpose, but with the advent of bone-supported arch bars (BSABs), more surgeons now prefer them to conventional EABs. The present study was designed to identify which of the two methods is best. An exhaustive literature search was conducted in June 2020 on various electronic databases to select studies that compared EABs and BSABs. Outcomes such as duration of placement, stability, oral hygiene, and complications such as damage to the roots of teeth and needle-stick injury, were analysed. A total of 716 studies were identified, of which seven were eligible for inclusion. The meta-analysis showed that the use of BSABs is significantly faster with no needle penetration and better oral hygiene. Both arch bars are equally stable, but root damage is an associated complication. The available literature to date shows that BSABs are a better option than EABs. However, further research is recommended, as these studies are associated with various confounding factors.

Breast Angiosarcoma Surveillance Study: UK national audit of management and outcomes of angiosarcoma of the breast and chest wall.

BACKGROUND: Breast angiosarcomas are rare tumours of vascular origin. Secondary angiosarcoma occurs following radiotherapy for breast cancer. Angiosarcomas have high recurrence and poor survival rates. This is concerning owing to the increasing use of adjuvant radiotherapy for the treatment of invasive breast cancer and ductal cancer in situ (DCIS), which could explain the rising incidence of angiosarcoma. Outcome data are limited and provide a poor evidence base for treatment. This paper presents a national, trainee-led, retrospective, multicentre study of a large angiosarcoma cohort. METHODS: Data for patients with a diagnosis of breast/chest wall angiosarcoma between 2000 and 2015 were collected retrospectively from 15 centres. RESULTS: The cohort included 183 patients with 34 primary and 149 secondary angiosarcomas. Median latency from breast cancer to secondary angiosarcoma was 6 years. Only 78.9 per cent of patients were discussed at a sarcoma multidisciplinary team meeting. Rates of recurrence were high with 14 of 28 (50 per cent ) recurrences in patients with primary and 80 of 124 (64.5 per cent ) in those with secondary angiosarcoma at 5 years. Many patients had multiple recurrences: total of 94 recurrences in 162 patients (58.0 per cent). Median survival was 5 (range 0-16) years for patients with primary and 5 (0-15) years for those with secondary angiosarcoma. Development of secondary angiosarcoma had a negative impact on predicted breast cancer survival, with a median 10-year PREDICT prognostic rate of 69.6 per cent, compared with 54.0 per cent in the observed cohort. CONCLUSION: A detrimental impact of secondary angiosarcoma on breast cancer survival has been demonstrated. Although not statistically significant, almost all excess deaths were attributable to angiosarcoma. The increased use of adjuvant radiotherapy to treat low-risk breast cancer and DCIS is a cause for concern and warrants further study.

A proposed ''A to Z RAM (Radiograph Assessment Method)'' for triage of patients with a suspected bone tumour.

INTRODUCTION: We propose a ''A to Z RAM (Radiograph Assessment Method)'' for evaluation of Radiograph of patients with a suspected bone tumour. METHODS: In the current study, ten radiological features with letters 'A, B, C, D, E, F and Z' were used and which included the age of the patient, involved part of the bone, characteristics, content, distinctiveness, the exterior of the bone, fracture, and zone of transition. Four independent observers (orthopaedic oncologists and surgical oncologists) evaluated a set of 30 radiographs of bone tumour selected at random from our hospital database based on A to Z RAM. We classified the lesions into two groups according to the traffic signal system; Green (suspected benign lesion) and Red (suspected malignant lesion). RESULTS: There were 18 (60%) benign bone lesions and 12 (40%) malignant lesions in the current study. 91.6% of malignant tumours and 88.8% of the benign tumours were identified correctly by the four observers. The inter-observer variability with Fleiss kappa was 0.884 (95% CI 0.7-1.03 p-value < 0.05), suggestive of agreement not by chance. These radiographs were again reassessed by the four observers after 3 months. The interobserver variability by Fleiss kappa was 1.0 (95% CI 0.8-1.1) suggesting complete agreement amongst the observers. Both orthopaedic oncologists had intra-observer kappa as 1.0 each and both surgical oncologists had 0.795 and 0.930 respectively. CONCLUSION: The proposed A to Z RAM is an easy to use and reproducible method for reviewing radiographs in the out-patient department along with clinical findings for better management of patients with suspected bone lesions. The A to Z RAM can be a medical triage tool and subdivide bone lesions into two subgroups i.e. suspected benign lesion with a suggestion of further investigations with MRI and biopsy and suspected malignant lesion with a suggestion of MRI or early referral to a tertiary cancer center with expertise in orthopaedic oncology. IMPLICATIONS FOR PRACTICE: The A to Z RAM (Radiologic Assessment Method) is a reproducible method for reviewing radiographs in the out-patient department and can be an aid for better management of patients. A to Z RAM is useful as a medical triage system, subdividing patients according to the probable diagnosis into a suspected benign lesion and suspected malignant lesion.

A novel post stamp technique for conservative management of OKC: Rai Technique.

A novel technique of Conservative management of OKCs via post stamp method of removing the buccal cortical plate of posterior mandible to expose the cystic lesion and carried out enucleation, curettage and chemical cauterization has been described in the present paper. Also the diseased bone has been used as a bone graft to maintain the contour deformity of the mandible. The present technique has been used in 9 patients with good quality of life and postoperative esthetic results with five years follow up.

A 10-year review of surgical management of dermatofibrosarcoma protuberans.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer. Standard treatment in the UK is either wide local excision (WLE) or Mohs micrographic surgery (MMS). It is unclear which approach has the lower recurrence rate. OBJECTIVES: We undertook a retrospective comparative review of surgical management of DFSP in the UK National Health Service in order to define (i) current surgical practice for primary and recurrent DFSP, (ii) local recurrence rates for primary DFSP and (iii) survival outcomes for DFSP. METHODS: A retrospective clinical case-note review of patients with histologically confirmed DFSP (January 2004 to December 2013) who have undergone surgical treatment. RESULTS: The surgical management of 483 primary and 64 recurrent DFSP in 11 plastic surgery and 15 dermatology departments was analysed. Almost 75% of primary DFSP (n = 362) were treated with WLE and 20% (n = 97) with MMS. For recurrent DFSP, 69% (n = 44) and 23% (n = 15) of patients underwent WLE and MMS, respectively. Recurrent primary DFSP occurred in six patients after WLE and none after MMS. The median follow-up time was 25·5 months (interquartile range 6·8-45·1) for new and 19·8 (IQR 4·5-44·5) for recurrent DFSP [Correction added on 1 Feb 2021, after first online publication: 4.8 years (interquartile range 3.5-5.8) was incorrect], with eight reported deaths during the follow-up analysis period (one confirmed to be DFSP related). CONCLUSIONS: WLE was the most common surgical modality used to treat DFSP across the UK. The local recurrence rate was very low, occurring only after WLE. Although a prospective randomized controlled trial may provide more definitive outcomes, in the absence of a clearly superior surgical modality, treatment decisions should be based on patient preference, clinical expertise and cost.

Incomplete surgical excision of keratinocyte skin cancers: a systematic review and meta-analysis.

BACKGROUND: Keratinocyte or nonmelanoma skin cancer (NMSC) is the commonest malignancy worldwide. The usual treatment is surgical excision. Current guidelines underestimate incomplete excision rates. OBJECTIVES: We aimed to determine the risk of incomplete excision of NMSCs through a systematic review and meta-analysis of primary clinical studies. METHODS: A PRISMA-compliant systematic review and meta-analysis was performed using methodology proposed by Cochrane (PROSPERO CRD42019157936). A comprehensive search strategy was applied to MEDLINE, Embase, Scopus, CINAHL, EMCare, Cochrane Library and the grey literature (January 2000-27 November 2019). All studies were included except those on Mohs micrographic surgery, frozen section or biopsies. Abstract screening and data extraction were performed in duplicate. Risk of bias was assessed using a tool for prevalence/incidence studies. The primary outcome was the proportion of incomplete surgical excisions. A random-effects model for pooling of binomial data was used. Differences between proportions were assessed by subgroup meta-analysis and meta-regression, which were presented as risk ratios (RRs). RESULTS: Searching identified 3477 records, with 110 studies included, comprising 53 796 patients with 106 832 basal cell carcinomas (BCCs) and 21 569 squamous cell carcinomas (SCCs). The proportion of incomplete excisions for BCC was 11·0% [95% confidence interval (CI) 9·7-12·4] and for SCC 9·4% (95% CI 7·6-11·4). Proportions of incomplete excisions by specialty were: dermatology, BCCs 6·2% and SCCs 4·7%; plastic surgery, BCCs 9·4% and SCCs 8·2%; general practitioners, BCCs 20·4% and SCCs 18·9%. The risk of incomplete excision for general practitioners was four times that of dermatologists for both BCCs (RR 3·9, 95% CI 2·0-7·3) and SCCs (RR 4·8, 95% CI 1·0-22·8). Studies were heterogeneous (I2  = 98%) and at high risk of bias. CONCLUSIONS: The proportion of incomplete excisions is higher than previously reported. Excisions performed by specialists may lower the risk of incomplete excision.

Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death.

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.