Management options for chronic anal fissure: a systematic review of randomised controlled trials.

INTRODUCTION: Anal fissure is the most common cause of severe anorectal pain in adults, contributing significantly to coloproctology workloads. There are a wide variety of management options available, including topical nitrites, calcium channel blockers, botulinum toxin injection and sphincterotomy. The aim of this study was to review current options for the treatment of chronic anal fissure. METHODS: A comprehensive search identifying randomized controlled trials comparing treatment options for anal fissure published between January 2000 and February 2020 was performed. The primary outcome assessed was healing at 8 weeks post commencing treatment. Secondary outcomes included recurrence, intolerance of treatment and complications. RESULTS: A total of 2822 studies were identified. After removal of duplicates and non-relevant studies, we identified nine randomized controlled trials which met pre-defined criteria. There was a total of 775 patients. At 8 weeks, healing rates were 95.13% in those treated with sphincterotomy, 66.7% in the botulinum toxin group, 63.8% in the nitrate group, 52.3% for topical diltiazem and 50% for topical minoxidil. Recurrence was highest amongst those treated with botulinum toxin injection (41.7%) and lowest for sphincterotomy (6.9%). Although the absolute number is low, there was a risk of permanent incontinence with sphincterotomy. CONCLUSION: This review of the randomized control data demonstrates that healing was significantly higher amongst those treated with sphincterotomy versus more conservative modalities. Topical nitrites had similar outcomes to botulinum toxin injection but were poorly tolerated in comparison to other treatments. The benefit of sphincterotomy was at a cost of increased complications, notably permanent incontinence.

Sigmoid Perforation Secondary to Accidental Ingestion of a Chicken Bone.

Presentation We describe an unusual presentation of sigmoid colon perforation secondary to an ingested chicken bone. Diagnosis The patient presented with a 4 day history of abdominal pain and distension. On examination there were signs of peritonism. Inflammatory markers were raised. Computed tomography revealed a linear density projecting through the wall of the colon. Treatment The patient underwent emergency laparotomy and a Hartmann's procedure. A chicken bone was found to be the causative foreign object. Conclusion Foreign body ingestion is an uncommon cause of sigmoid perforation which may mimic more common surgical presentations such as diverticulitis.

Prophylactic negative wound therapy in laparotomy wounds (PROPEL trial): randomized controlled trial.

BACKGROUND: Superficial surgical site infections are a common post-operative complication. They also place a considerable financial burden on healthcare. The use of prophylactic negative pressure wound therapy has been advocated to reduce wound infection rates. However, there is debate around its routine use. The purpose of this trial is to determine if prophylactic negative pressure wound therapy reduces post-operative wound complications in patients undergoing laparotomy. METHODS/DESIGN: This multi-centre randomised controlled trial will compare standard surgical dressings (control) to two competing negative pressure wound therapy dressings (Prevena™ and PICO™). All patients will be over 18 years, who are undergoing an emergency or elective laparotomy. It is intended to enrol a total of 271 patients for the trial. DISCUSSION: The PROPEL trial is a multi-centre randomised controlled trial of patients undergoing laparotomy. The comparison of standard treatment to two commercially available NPWT will help provide consensus on the routine management of laparotomy wounds. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT number NCT03871023).

Genetic counselors' (GC) knowledge, awareness, understanding of clinical next-generation sequencing (NGS) genomic testing.

Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next-generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer-related counseling, exposure to NGS testing, and NGS-focused education. Substantial disagreement about the role of counseling for tumor-based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation.

A pathway to empowerment: evaluating a cancer education and support programme in New Zealand.

Support programmes often benefit cancer patients and their families. This study evaluates how the Living Well Cancer Education Programme (LWCEP), from the Cancer Society of New Zealand, meets the needs of its clients. A purposeful sample of 21 participants representing the normal range of demographic characteristics (age, gender, diagnosis and geographical location) for the programme, participated in semi-structured interviews. Demographic data were subjected to a frequency analysis. Main data were collected and analysed using a constructivist grounded theory approach regarding the experiences of the participants with being on the programme and recommendations for future development. Of the 21 participants, 14 were cancer patients (eight women and six men) and seven were support people (five women and two men). The LWCEP was described as a safe, supportive and stimulating environment, provided a powerful sense of belonging, empowered participants to gain perspective, enhance their confidence and communication skills and make increasingly informed choices. Consistent with a previous evaluation focussing on the facilitators of the LWCEP, there was a strong desire for better promotion of the programme to the wider community, establishment of a better referral pathway and the potential to offer two separate programmes depending on the stage of a patient's journey.

Technical and functional design considerations for a real-world interpretable AI solution for NIR perfusion analysis (including cancer).

Near infrared (NIR) analysis of tissue perfusion via indocyanine green fluorescence assessment is performed clinically during surgery for a range of indications. Its usefulness can potentially be further enhanced through the application of interpretable artificial intelligence (AI) methods to improve dynamic interpretation accuracy in these and also open new applications. While its main use currently is for perfusion assessment as a tissue health check prior to performing an anastomosis, there is increasing interest in using fluorophores for cancer detection during surgical interventions with most research being based on the paradigm of static imaging for fluorophore uptake hours after preoperative dosing. Although some image boosting and relative estimation of fluorescence signals is already inbuilt into commercial NIR systems, fuller implementation of AI methods can enable actionable predictions especially when applied during the dynamic, early inflow-outflow phase that occurs seconds to minutes after ICG (or indeed other fluorophore) administration. Already research has shown that such methods can accurately differentiate cancer from benign tissue in the operating theatre in real time in principle based on their differential signalling and could be useful for tissue perfusion classification more generally. This can be achieved through the generation of fluorescence intensity curves from an intra-operative NIR video stream. These curves are processed to adjust for image disturbances and curve features known to be influential in tissue characterisation are extracted. Existing machine learning based classifiers can then use these features to classify the tissue in question according to prior training sets. The use of this interpretable methodology enables accurate classification algorithms to be built with modest training sets in comparison to those required for deep learning modelling in addition to achieving compliance with medical device regulations. Integration of the multiple algorithms required to achieve this classification into a desktop application or medical device could make the use of this method accessible and useful to (as well as useable by) surgeons without prior training in computer technology. This document details some technical and functional design considerations underlying such a novel recommender system to advance the foundational concept and methodology as software as medical device for in situ cancer characterisation with relevance more broadly also to other tissue perfusion applications.

The impact of in-service physical injury or illness on the mental health of military veterans.

BACKGROUND: Each year approximately 2000 UK service personnel are medically discharged with physical and/or psychological injury or illness. While there is much research on both psychological injury and physical injury, the challenges of transition relating to the intersection between the two has received less attention. This article reports on the first phase of a 2-year funded study with the aim to understand the lived experiences of veterans who have been discharged from service with a physical injury or illness and the impacts of this on their mental health. METHODS: Using a qualitative methodology, 22 veterans who had been discharged from service within the last 8 years were interviewed to identify key aspects of their experience of the transition process. RESULTS: The article highlights two key themes: how some veterans adjusted to life with a physical injury or condition; and, the intersections that became apparent between physical injury and mental health. The challenges that veterans faced were shaped by the transition process and by the way in which the medical discharge process was conducted. CONCLUSIONS: Consideration of improvements to the medical discharge process could influence better outcomes for those who have left with a physical injury or illness and later find themselves struggling with mental health issues.

Extended pelvic resections for recurrent or persistent uterine and cervical malignancies: an update on out of the box surgery.

OBJECTIVE: To update our report on the outcome of patients who underwent extended pelvic resection (EPR) for recurrent or persistent uterine and cervical malignancies. METHODS: We reviewed the records of all patients who underwent EPR between 6/2000 and 07/2011. EPR was defined as an en-bloc resection of a pelvic tumor with sidewall muscle, bone, major nerve, and/or major vascular structure. Complications up to 180 days post surgery were analyzed. Survivals were estimated using the Kaplan-Meier method. RESULTS: We identified 22 patients. Median age at the time of EPR was 58 years (range, 36-74). Median tumor diameter was 5.4 cm (range, 1.5-11.2). Primary tumor sites included: uterus, 13; cervix, 7; synchronous uterus/cervix, 1; and synchronous uterus/ovary, 1. The EPR structures were: muscle, 13; nerve, 10; bone, 8; vessel, 5. Complete gross resection with microscopically negative margins (R0 resection) was achieved in 17 patients (77%). There were no perioperative mortalities. Major postoperative complications occurred in 14 patients (64%). The two most common morbidities were pelvic abscesses and peripheral neuropathies. Median follow-up time was 28 months (range, 6-99). The 5-year overall survival (OS) for the entire cohort was 34% (95% CI, 13-57). For the 17 patients who had an R0 resection, the 5-year OS was 48% (95% CI, 19-73). In patients with positive pathologic margins (n=5), the 5-year OS was 0%. CONCLUSION: EPR was associated with prolonged survival when an R0 resection was achieved. The high rate of postoperative complications remains a hallmark of these procedures and properly selected patients should be extensively counseled preoperatively.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.

In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses, leading to a secondarily avascular tumor and massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth.

The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons.

The pattern of retrograde axonal transport of the target-derived neurotrophic molecule, nerve growth factor (NGF), correlates with its trophic actions in adult neurons. We have determined that the NGF-related neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are also retrogradely transported by distinct populations of peripheral and central nervous system neurons in the adult. All three 125I-labeled neurotrophins are retrogradely transported to sites previously shown to contain neurotrophin-responsive neurons as assessed in vitro, such as dorsal root ganglion and basal forebrain neurons. The patterns of transport also indicate the existence of neuronal populations that selectively transport NT-3 and/or BDNF, but not NGF, such as spinal cord motor neurons, neurons in the entorhinal cortex, thalamus, and neurons within the hippocampus itself. Our observations suggest that neurotrophins are transported by overlapping as well as distinct populations of neurons when injected into a given target field. Retrograde transport may thus be predictive of neuronal types selectively responsive to either BDNF or NT-3 in the adult, as first demonstrated for NGF.

Extended pelvic resections for recurrent uterine and cervical cancer: out-of-the-box surgery.

Patients with recurrent uterine and cervical cancer have poor prognoses. The objective of this study was to analyze the outcomes of patients with recurrent uterine and cervical cancer who had undergone attempted curative resection of pelvic bone, sidewall muscle, major blood vessels, and/or nerves. We reviewed the records of all 14 patients with recurrent uterine and cervical cancer who had extended pelvic resections at our institution between June 2000 and November 2006. Primary sites of disease were the uterus (11 patients) and cervix (3 patients). Tumor histology was as follows: adenocarcinoma, seven; squamous cell carcinoma, three; leiomyosarcoma, three; and adenosarcoma, one. Previous treatment included hysterectomy, 11; pelvic radiation, 9; chemotherapy, 9; and total pelvic exenteration, 2. Extended pelvic resections included removal of pelvic sidewall muscle, five; bone, five; common and/or external iliac vessel, five; femoral nerve, two; lumbosacral nerve root, one; and obturator nerve, one. Other procedures included total pelvic exenteration, three; posterior exenteration, two; and anterior exenteration, one. Complete resection with negative margins was obtained in 11 (78%) of 14 patients. Seven patients (50%) received high-dose rate intraoperative radiation therapy. Reconstructive procedures included continent or incontinent urinary diversion, four; femoral-femoral arterial bypass, two; myocutaneous flap, two; and urinary ileal interposition, one. Median total operating time was 628 min (range, 345-935 min) and median estimated blood loss was 900 mL (range, 300-16,000 mL). Seven patients (50%) had one or more major complication(s), including pelvic abscess, three; colonic fistula, two; massive intraoperative hemorrhage, one; postoperative bladder perforation, one; thrombosed femoral-femoral graft, one; and disruption of appendicocutaneous urinary anastomosis, one. At a median follow-up of 26 months (range, 5-84 months), ten patients (71%) are alive and four patients (29%) have died of disease at 8, 13, 33, and 42 months postoperatively.

Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: Evidence-based review of patient selection and treatment algorithms.

Cytoreduction and heated intraperitoneal chemotherapy (CS/HIPEC) is increasingly utilized as a treatment strategy for patients with peritoneal metastases from various primary tumor sites. For this heterogenous procedure, related to patient characteristics, patient selection, and the extent of surgical completeness of cytoreduction, high level evidence (ex: multiple randomized controlled trials) is not available to support efficacy. This review of the available literature supporting application of the procedure, focusing on colorectal cancer, provides a summary of current evidence for patient selection and treatment algorithms based on patient presentation.

Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma, in children and young adults.

PURPOSE: To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma), while testing the feasibility of intensive use in adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV). PATIENTS AND METHODS: This report concerns previously untreated patients with newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100 cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140 mg/kg per course for patients < 10 years old), plus 72-hour infusions of doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are used. Courses start after neutrophil counts reach 500/microL and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radiotherapy follows completion of all chemotherapy. RESULTS: Among the first 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patients and partial responses (PRs) in two patients. For 24 patients with locoregional disease, the 2-year event-free survival rate was 77%; adverse events were two locoregional relapses, one distant relapse, and one secondary leukemia. All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are not assessable in terms of long-term efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone marrow transplantation), or septic death (autopsy showed no residual pPNET). All six patients with widespread metastases had major responses, including eradication of extensive bone marrow involvement, but distant relapses ensued. Myelosuppression was severe, but most patients received the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic toxicities were mucositis and peripheral neuropathy. CONCLUSION: Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in young adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge.

Acetabular development after bipolar hemiarthroplasty for osteosarcoma in children.

A retrospective analysis was performed of eight patients with an open triradiate cartilage, who underwent resection for osteosarcoma and reconstruction of the proximal femur with a hemiarthroplasty, in order to identify changes of acetabular development. An analysis of the centre-edge angle, teardrop-to-medial prosthesis distance, superior joint space, teardrop-to-superior prosthesis distance, degree of lateral translation, and arthritic changes, was performed on serial radiographs. The median age at the time of the initial surgery was 11 years (5 to 14). All patients developed progressive superior and lateral migration of the prosthetic femoral head. Following hemiarthroplasty in the immature acetabulum, the normal deepening and enlargement of the acetabulum is arrested. The degree of superior and lateral migration of the prosthetic head depends on the age at diagnosis and the length of follow-up.

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

Low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes): report of a case that metastasized.

"Hyalinizing spindle cell tumor with giant rosettes" is a tumor recently described by Lane et al. and thought by them possibly to represent a form of low-grade fibromyxoid sarcoma. Proof of a metastatic potential was lacking. We report an example of this tumor on the arm of a 28-year-old woman. The ultrastructural study of the tumor confirmed the fibroblastic nature of the lesion, which subsequently metastasized to the lung. Histologically, the giant rosettes simulated palisaded granulomas. Our findings warrant classifying the tumor as a sarcoma, and we suggest the designation low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes).