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Clinical Gastroenterology and... Jun 2024Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and... (Review)
Review
BACKGROUND AND AIMS
Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium.
METHODS
We conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach.
RESULTS
Of 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on six structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with longstanding (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus(SCCA) and anorectal carcinoma. Risk factors for SCCA, notably human papilloma virus (HPV), should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an exam under anesthesia (EUA) with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers.
CONCLUSION
Inflammatory bowel disease (IBD) clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.
PubMed: 38871152
DOI: 10.1016/j.cgh.2024.05.029 -
Ultrasound in Obstetrics & Gynecology :... Oct 2023The primary objective was to perform a systematic review of predictive factors for obstetric anal sphincter injury (OASI) occurrence at first vaginal delivery, with the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The primary objective was to perform a systematic review of predictive factors for obstetric anal sphincter injury (OASI) occurrence at first vaginal delivery, with the diagnosis made by ultrasound (US-OASI). The secondary objective was to report on incidence rates of sonographic anal sphincter (AS) trauma, including trauma that was not clinically reported at childbirth, among the studies providing data for our primary objective.
METHODS
We conducted a systematic search of MEDLINE, EMBASE, Web of Science, CINAHL, The Cochrane Library and ClinicalTrials.gov databases. Both observational cohort studies and interventional trials were eligible for inclusion. Study eligibility was assessed independently by two authors. Random-effects meta-analyses were performed to pool effect estimates from studies reporting on similar predictive factors. Summary odds ratio (OR) or mean difference (MD) is reported with 95% CI. Heterogeneity was assessed using the I statistic. Methodological quality was assessed using the Quality in Prognosis Studies tool.
RESULTS
A total of 2805 records were screened and 21 met the inclusion criteria (16 prospective cohort studies, three retrospective cohort studies and two interventional non-randomized trials). Increasing gestational age at delivery (MD, 0.34 (95% CI, 0.04-0.64) weeks), shorter antepartum perineal body length (MD, -0.60 (95% CI, -1.09 to -0.11) cm), labor augmentation (OR, 1.81 (95% CI, 1.21-2.71)), instrumental delivery (OR, 2.13 (95% CI, 1.13-4.01)), in particular forceps extraction (OR, 3.56 (95% CI, 1.31-9.67)), shoulder dystocia (OR, 12.07 (95% CI, 1.06-137.60)), episiotomy use (OR, 1.85 (95% CI, 1.11-3.06)) and shorter episiotomy length (MD, -0.40 (95% CI, -0.75 to -0.05) cm) were associated with US-OASI. When pooling incidence rates, 26% (95% CI, 20-32%) of women who had a first vaginal delivery had US-OASI (20 studies; I = 88%). In studies reporting on both clinical and US-OASI rates, 20% (95% CI, 14-28%) of women had AS trauma on ultrasound that was not reported clinically at childbirth (16 studies; I = 90%). No differences were found in maternal age, body mass index, weight, subpubic arch angle, induction of labor, epidural analgesia, episiotomy angle, duration of first/second/active-second stages of labor, vacuum extraction, neonatal birth weight or head circumference between cases with and those without US-OASI. Antenatal perineal massage and use of an intrapartum pelvic floor muscle dilator did not affect the odds of US-OASI. Most (81%) studies were judged to be at high risk of bias in at least one domain and only four (19%) studies had an overall low risk of bias.
CONCLUSION
Given the ultrasound evidence of structural damage to the AS in 26% of women following a first vaginal delivery, clinicians should have a low threshold of suspicion for the condition. This systematic review identified several predictive factors for this. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Anal Canal; Retrospective Studies; Prospective Studies; Delivery, Obstetric; Episiotomy; Anus Diseases; Perineum; Risk Factors; Obstetric Labor Complications
PubMed: 37329513
DOI: 10.1002/uog.26292 -
Asian Journal of Surgery Oct 2023
Topics: Humans; Anus Neoplasms; Rectal Fistula; Anal Canal; Treatment Outcome
PubMed: 37344312
DOI: 10.1016/j.asjsur.2023.05.085 -
Cancer Aug 2023Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers...
BACKGROUND
Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes.
METHODS
Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors.
RESULTS
On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV.
CONCLUSIONS
Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients.
PLAIN LANGUAGE SUMMARY
Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.
Topics: Female; Humans; Male; Middle Aged; Anus Neoplasms; Biomarkers; Carcinoma, Squamous Cell; Cytochrome P-450 CYP2D6; DNA Copy Number Variations; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies
PubMed: 37096763
DOI: 10.1002/cncr.34797 -
Colorectal Disease : the Official... Dec 2023The management of anal fissure: ACPGBI position statement was written 15 years ago. [KLR Cross et al., Colorectal Dis, 2008]. Our aim was to update the guideline and... (Review)
Review
AIM
The management of anal fissure: ACPGBI position statement was written 15 years ago. [KLR Cross et al., Colorectal Dis, 2008]. Our aim was to update the guideline and provide recommendations on the most effective treatment for patients with anal fissures utilising a multidisciplinary, rigorous guideline methodology.
METHODS
The development process consisted of six phases. In phase 1 we defined the scope of the guideline. The patient population included patients with acute and chronic anal fissure. The target group was all practitioners (primary and secondary care) treating patients with fissures and, in addition, healthcare workers and patients who desired information regarding fissure management. In phase 2 we formed a guideline development group (GDG) including a methodologist. In phase 3 review questions were formulated, using a reversed PICO process, starting with possible recommendations based on the GDG's knowledge. In phase 4 a comprehensive literature search focused on existing systematic reviews addressing each review question, supplemented by more recent studies if appropriate. In phase 5 data were extracted from the included papers and checked by the GDG. If indicated, meta-analysis of systematic review data was updated by the GDG. During phase 6 the GDG members decided what recommendations could be made based on the evidence in the literature and strength of the recommendation was assessed using 'grade'.
RESULTS
This guideline is divided into two sections: Primary care which includes (i) diagnosis; (ii) basic treatment; (iii) topical treatment; and secondary care which includes (iv) botulinum toxin therapy; (v) surgical intervention and (vi) special situations (including pregnancy and breast-feeding patients, children, receptive anal intercourse and low-pressure fissures). A total of 23 recommendations were formulated. A new term clinically healed was described by the GDG.
CONCLUSION
This guideline provides an up-to-date evidence-based summary of the current knowledge of the management of anal fissure and may serve as a useful guide for clinicians as well as a potential reference for patients.
Topics: Child; Humans; Chronic Disease; Fissure in Ano; Treatment Outcome; United Kingdom
PubMed: 37926920
DOI: 10.1111/codi.16762 -
Journal of Pediatric Surgery Jun 2024Pediatric patients with perianal Crohn's Disease (CD) suffer recalcitrant fistulas, abscesses, and strictures. Fecal diversion is a palliative last resort, but the...
INTRODUCTION
Pediatric patients with perianal Crohn's Disease (CD) suffer recalcitrant fistulas, abscesses, and strictures. Fecal diversion is a palliative last resort, but the expected clinical course and long-term management of the ostomy for this population is unclear. We sought to identify factors predictive of ostomy takedown and establish management recommendations for fistulizing and stenosing disease.
METHODS
We reviewed our institutional registry for patients aged 1-18 years with CD who received perianal surgery from 2011 to 2021. We analyzed medical therapy, examinations under anesthesia (EUA), fistula and stenosis response, and rates of fecal diversion and reversal.
RESULTS
There were 109 patients with fistulizing CD and 21 with stenosing CD. There were 8 diverted for fistula and 4 due to stricture [8/109 (7 %) vs 4/21 (19 %), p = 0.213]. Three patients with fistulizing disease had their ostomy reversed at an average of 1.46 years. Each demonstrated consistent CD control and with no additional perianal flares. The remainder have been diverted 3.15 ± 4.57 years with 2.1 ± 2.8 EUAs. Only one patient with stricture was durably reversed, but they still require serial anal dilation. Two were reversed but required re-diversion due to stricture progression.
CONCLUSION
Reversal rates after fecal diversion for pediatric perianal CD remain disappointingly low and diversion does not obviate the possibility of future EUAs. While reversal was successful for medically responsive patients with fistulizing disease, those with stenosing disease remained dependent on anal dilations and were more likely to fail reversal. Fecal diversion does nothing to reverse an established stricture and such patients will likely need to decide between indefinite dilations or permanent ostomy.
LEVEL OF EVIDENCE
IV.
TYPE OF STUDY
Retrospective review.
Topics: Humans; Crohn Disease; Child; Adolescent; Male; Female; Child, Preschool; Retrospective Studies; Infant; Ostomy; Constriction, Pathologic; Rectal Fistula; Anus Diseases
PubMed: 38104035
DOI: 10.1016/j.jpedsurg.2023.11.009 -
Biomedicine & Pharmacotherapy =... Oct 2023As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular...
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.
Topics: Mice; Animals; Atorvastatin; Endothelial Cells; Ubiquitination; Ubiquitin-Protein Ligases; Mice, Knockout; Hypertension
PubMed: 37557013
DOI: 10.1016/j.biopha.2023.115228 -
Journal of the American Veterinary... Oct 2023To evaluate short- and long-term outcomes for dogs undergoing anal sacculectomy for massive (> 5 cm) apocrine gland anal sac adenocarcinoma (AGASACA).
OBJECTIVE
To evaluate short- and long-term outcomes for dogs undergoing anal sacculectomy for massive (> 5 cm) apocrine gland anal sac adenocarcinoma (AGASACA).
ANIMALS
28 client-owned dogs with massive AGASACA.
PROCEDURES
A retrospective multi-institutional study was performed. Pre-, intra-, and post-operative data was collected, and variables were statistically analyzed for associations with progression-free interval (PFI) and overall survival (OS).
RESULTS
At the time of anal sacculectomy, 19 (68%) dogs underwent concurrent iliosacral lymph node extirpation, including 17 of 18 (94%) dogs with suspected nodal metastasis preoperatively. Five (18%) dogs experienced grade 2 intraoperative complications. Ten (36%) dogs experienced postoperative complications, including 1 grade 3 and 1 grade 4 complication. No dogs had permanent fecal incontinence, tenesmus, or anal stenosis. Nineteen dogs received adjuvant chemotherapy, radiation, or both. Local recurrence occurred in 37% of dogs. Dogs with lymph node metastasis at surgery were more likely than dogs without metastasis to develop new/progressive lymph node metastasis (10/17 [59%] vs 0/10 [0%]; P = .003) and distant metastasis (7/17 [41%] vs 0/10 [0%]; P = .026). Median PFI was 204 days (95% CI, 145 to 392). Median OS was 671 days (95% CI, 225 to upper limit not reached). Nodal metastasis at the time of surgery was associated with shorter PFI (P = .017) but not OS (P = .26). Adjuvant therapy was not associated with outcome.
CLINICAL RELEVANCE
Dogs with massive AGASACA experienced prolonged survival following anal sacculectomy despite a high incidence of local recurrence and metastasis. Lymph node metastasis at the time of surgery was a negative prognostic indicator for PFI but not OS.
Topics: Animals; Dogs; Adenocarcinoma; Anal Gland Neoplasms; Anal Sacs; Apocrine Glands; Dog Diseases; Lymphatic Metastasis; Retrospective Studies
PubMed: 37225157
DOI: 10.2460/javma.23.02.0102 -
The New England Journal of Medicine Apr 2024
Topics: Humans; Antineoplastic Agents; Antiviral Agents; Anus Neoplasms; Betapapillomavirus; Carcinoma, Squamous Cell; Receptors, CXCR4; Papillomavirus Infections; Primary Immunodeficiency Diseases; Warts; Gain of Function Mutation
PubMed: 38598804
DOI: 10.1056/NEJMc2213180 -
Frontiers in Oncology 2023Colorectal cancer (CRC) is a globally significant health concern, necessitating effective preventive strategies through identifying modifiable risk factors....
BACKGROUND
Colorectal cancer (CRC) is a globally significant health concern, necessitating effective preventive strategies through identifying modifiable risk factors. Constipation, characterized by infrequent bowel movements or difficulty passing stools, has been proposed as a potential CRC risk factor. However, establishing causal links between constipation and CRC remains challenging due to observational study limitations.
METHODS
Mendelian randomization (MR) utilizes genetic variants as instrumental variables, capitalizing on genetically determined variation to assess causal relationships. In this dual-sample bidirectional MR study, we extracted genetic data from independent cohorts with CRC (Include colon cancer and rectal cancer) and constipation cases. Genome-wide association studies (GWAS) identified constipation and CRC-associated genetic variants used as instruments to infer causality. The bidirectional MR analysis evaluated constipation's impact on CRC risk and the possibility of reverse causation.
RESULTS
Employing bidirectional MR, we explored the causal relationship between constipation and CRC using publicly available GWAS data. Analysis of constipation's effect on CRC identified 26 significant SNPs, all with strong instrumental validity. IVW-random effect analysis suggested a potential causal link [ = 1.002(1.000, 1.004); = 0.023], although alternative MR approaches were inconclusive. Investigating CRC's impact on constipation, 28 significant SNPs were identified, yet IVW analyses found no causal effect [ = 0.137(0.007, 2.824); = 0.198]. Other MR methods also yielded no significant causal association. We analyzed constipation separately from colon and rectal cancer using the same methodology in both directions, and no causal relationship was obtained.
CONCLUSION
Our bidirectional MR study suggests a potential constipation-CRC link, with mixed MR approach outcomes. Limited evidence supports constipation causing CRC. Reliable instruments, minimal heterogeneity, and robust analyses bolster these findings, enriching understanding. Future research should explore additional factors to enhance comprehension and clinical implications.
PubMed: 38044987
DOI: 10.3389/fonc.2023.1282066