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Journal of Clinical Oncology : Official... Jul 2023The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions.
METHODS
PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N-, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL).
RESULTS
From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted < .05). Neither bladder function nor HRQL differed between groups at any time point.
CONCLUSION
For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.
Topics: Adult; Humans; Anal Canal; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Organ Sparing Treatments; Rectal Neoplasms; Fluorouracil; Neoadjuvant Therapy; Patient Reported Outcome Measures; Leucovorin; Treatment Outcome
PubMed: 37270691
DOI: 10.1200/JCO.23.00903 -
Gastroenterology Clinics of North... Mar 2024Anal cancer, mainly squamous cell carcinoma, is rare but increasing in prevalence, as is its precursor lesion, anal squamous dysplasia. They are both strongly associated... (Review)
Review
Anal cancer, mainly squamous cell carcinoma, is rare but increasing in prevalence, as is its precursor lesion, anal squamous dysplasia. They are both strongly associated with human papillomavirus infection. The 2-tiered Lower Anogenital Squamous Terminology classification, low-grade SIL and high-grade SIL, is preferred to the 3-tiered anal intraepithelial neoplasia classification because of better interobserver agreement and clearer management implications. Immunohistochemistry with p16 is helpful to corroborate the diagnosis of squamous dysplasia. Similarly, immunohistochemistry is helpful to differentiate primary Paget disease from secondary Paget disease, which is usually due to anal squamous mucosal/epidermal involvement by primary rectal adenocarcinoma.
Topics: Humans; Immunohistochemistry; Carcinoma, Squamous Cell; Anal Canal; Carcinoma in Situ; Papillomavirus Infections; Anus Neoplasms
PubMed: 38280748
DOI: 10.1016/j.gtc.2023.09.007 -
Science Advances Sep 2023Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma...
Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.
Topics: Animals; Humans; Mice; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Sorting Nexins; Stem Cells
PubMed: 37647408
DOI: 10.1126/sciadv.adh5016 -
Journal of Translational Internal... Jul 2023The aim of this systemtic review is to introduce clinical applications (especially emerging) and potential mechanisms of sacral nerve stimulation (SNS) for treating...
BACKGROUND
The aim of this systemtic review is to introduce clinical applications (especially emerging) and potential mechanisms of sacral nerve stimulation (SNS) for treating various gastrointestinal diseases.
MATERIALS AND METHODS
PubMed and Web of Science were searched for studies published on SNS and its clinical applications in fecal incontinence (limited to systematic review and meta-analysis of clinical studies), constipation (limited to reviews and randomized control clinical studies), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and upper gastrointestinal motility disorders. The relevant studies were pooled, and their findings were summarized and discussed.
RESULTS
SNS is an approved method for treating fecal incontinence. Systematic review and meta-analysis demonstrated high efficacy of the SNS therapy for fecal incontinence. Increased anal sphincter pressure and improvement in rectal sensation were reported as major mechanisms involved in the SNS therapy. SNS has also been proposed for treating constipation, but the therapy has been shown ineffective. There is a lack in SNS methodological optimization and mechanistic research. A few basic and clinical studies have reported the potential of SNS for treating visceral pain in IBS. SNS seemed capable of improving mucosal barrier functions. Several case reports are available in the literature on the treatment of IBD with SNS. Several laboratory studies suggested therapeutic potential of a special method of SNS for IBD. Cholinergic anti-inflammatory mechanisms were reported. Due to a recently reported spinal afferent and vagal efferent pathway of SNS, a few preclinical studies reported the potential of SNS for upper gastrointestinal motility disorders. However, no clinical studies have been performed.
CONCLUSIONS
SNS for fecal incontinence is a well-established clinical therapy. However, the current method of SNS is ineffective for treating constipation. Further methodological development and randomized clinical trials are needed to explore potential applications of SNS for IBS and IBD.
PubMed: 37408571
DOI: 10.2478/jtim-2023-0086 -
The Journal of Investigative Dermatology Aug 2023Mucous membrane pemphigoid is an autoimmune disease with variable clinical presentation and multiple autoantigens. To determine whether disease endotypes could be...
Mucous membrane pemphigoid is an autoimmune disease with variable clinical presentation and multiple autoantigens. To determine whether disease endotypes could be identified on the basis of the pattern of serum reactivity, the clinical and diagnostic information of 70 patients with mucous membrane pemphigoid was collected, and reactivity to dermal or epidermal antigens, using indirect immunofluorescence, and specific reactivity to bullous pemphigoid (BP) autoantigens BP180 and BP230, collagen VII, and laminin 332 were evaluated. Most patients had lesions at multiple mucosae, with the most prevalent being oropharyngeal (mouth, gingiva, pharynx; 98.6%), followed by ocular (38.6%), nasal (32.9%), genital or anal (31.4%), laryngeal (20%), and esophageal (2.9%) sites and skin (45.7%). Autoantigen profiling identified BP180 (71%) as the most common autoantigen, followed by laminin 332 (21.7%), collagen VII (13%), and BP230 IgG (11.6%). Reactivity to dermal antigens predicted a more severe disease characterized by a higher number of total sites involved, especially high-risk sites, and a decreased response to rituximab. In most cases, identification of dermal indirect immunofluorescence reactivity is an accurate predictor of disease course; however, confirmation of laminin 332 reactivity is important, with dermal indirect immunofluorescence positivity because of an increased risk of solid tumors. In addition, the ocular mucosae should be monitored in patients with IgA on direct immunofluorescence.
Topics: Humans; Pemphigoid, Bullous; Autoantibodies; Collagen; Autoantigens; Mucous Membrane; Non-Fibrillar Collagens; Pemphigoid, Benign Mucous Membrane
PubMed: 36870557
DOI: 10.1016/j.jid.2023.02.012 -
Cureus Nov 2023Anorectal mucosal melanoma (AMM) is an infrequent and highly aggressive form of mucosal melanoma. Its rarity makes it challenging to clinically diagnose, and its initial...
Anorectal mucosal melanoma (AMM) is an infrequent and highly aggressive form of mucosal melanoma. Its rarity makes it challenging to clinically diagnose, and its initial symptoms are typically nonspecific such as rectal/anal bleeding (the most common symptom), anal pain, or the presence of an anal mass. The prognosis for this condition is generally poor, and its incidence appears to be increasing each year. AMMs often go undetected and/or are already metastasized at the time of diagnosis. We present a case report of a patient who initially presented with nonspecific symptoms of anemia and blood per rectum, and was later found to have stage IV melanoma of the anorectal region. There is a notable scarcity of literature on this disease, resulting in a lack of a comprehensive understanding of its nature. Most available information consists of isolated case reports rather than comprehensive studies. Although surgical resection remains the primary treatment approach, the majority of patients (over 80%) will die due to distant metastasis within five years after undergoing surgery. The five-year survival rate for anorectal melanoma is estimated to be between 6% and 22%.
PubMed: 38106750
DOI: 10.7759/cureus.48835 -
Surgical Case Reports May 2024The rectal and vaginal walls are typically sutured if severe perineal lacerations with rectal mucosal damage occur during vaginal delivery. In case of anal incontinence...
BACKGROUND
The rectal and vaginal walls are typically sutured if severe perineal lacerations with rectal mucosal damage occur during vaginal delivery. In case of anal incontinence after the repair, re-suturing of the anal sphincter muscle is standard procedure. However, this procedure may not result in sufficient improvement of function.
CASE PRESENTATION
A 41-year-old woman underwent suture repair of the vaginal and rectal walls for fourth-degree perineal laceration at delivery. She was referred to our department after complaining of flatus and fecal incontinence. Her Wexner score was 15 points. Examination revealed decreased anal tonus and weak contractions on the ventral side. We diagnosed anal incontinence due to sphincter dysfunction after repair of a perineal laceration at delivery. We subsequently performed sphincter re-suturing with perineoplasty to restructure the perineal body by suturing the fascia located lateral to the perineal body and running in a ventral-dorsal direction, which filled the space between the anus and vagina and increased anal tonus. One month after surgery, the symptoms of anal incontinence disappeared (the Wexner score lowered to 0 points), and the anorectal manometry values increased compared to the preoperative values. According to recent reports on the anatomy of the female perineal region, bulbospongiosus muscle in women does not move toward the midline to attach to the perineal body, as has been previously believed. Instead, it attaches to the ipsilateral surface of the external anal sphincter. We consider the fascia lateral to the perineal body to be the fascia of the bulbospongiosus muscle.
CONCLUSIONS
In a case of postpartum anal incontinence due to sphincter dysfunction after repair of severe perineal laceration, perineoplasty with re-suturing an anal sphincter muscle resulted in improvement in anal sphincter function. Compared to conventional simple suture repair of the rectal wall only, this surgical technique may improve sphincter function to a greater degree.
PubMed: 38724859
DOI: 10.1186/s40792-024-01917-7 -
Emerging Infectious Diseases Oct 2023We investigated Treponema pallidum PCR positivity at mucosal sites (oral, anal, and vaginal sites) among adults who had sexual contact with a person with syphilis...
We investigated Treponema pallidum PCR positivity at mucosal sites (oral, anal, and vaginal sites) among adults who had sexual contact with a person with syphilis (syphilis contacts). All syphilis contacts had oral rinse and swab samples collected for testing. Men who have sex with men had anal swab and women had vaginal swab samples collected for testing, regardless of the presence of lesions. Of 407 persons tested, 42 (10%) had early syphilis diagnosed; of those, 19 (45%) tested positive by PCR from any anatomic site and had a positive serologic test. T. pallidum was positive from vaginal samples in 3 women, anal samples in 3 men, and oral cavity samples in 2 women and 3 men, without symptoms at those sites. Three women had no prior syphilis serologic test. T. pallidum detection at asymptomatic mucosal sites suggests early syphilis infections, particularly in cases that would conventionally be staged as latent syphilis of unknown duration.
Topics: Male; Adult; Female; Humans; Treponema pallidum; Syphilis; Homosexuality, Male; Sexual and Gender Minorities; Vagina
PubMed: 37703891
DOI: 10.3201/eid2910.230660 -
Techniques in Coloproctology Dec 2023Anal intraepithelial neoplasia (AIN) appears in three different stages. AIN 1 and AIN 2 (p16 negative) are defined as low risk and unlikely to progress to invasive...
BACKGROUND
Anal intraepithelial neoplasia (AIN) appears in three different stages. AIN 1 and AIN 2 (p16 negative) are defined as low risk and unlikely to progress to invasive anal cancer. AIN 2 (p16 positive) and AIN 3 are of high risk and should be treated because progression rates to anal cancer are around 10% and treatment significantly reduces this risk. The correct treatment is still a matter of debate. Human papilloma virus (HPV) plays a role in the development of AIN. Our aim was to assess anal endoscopic dissection (aESD) as an intervention for AIN3.
METHODS
We retrospectively evaluated patients who underwent aESD for AIN 3 between December 2017 and March 2023. The interventional technique itself (duration, complications, size of specimen) and patient outcomes (recurrence, progression to anal cancer, re-intervention) were analyzed.
RESULTS
Fifteen patients with a median age of 52 years (23-78) underwent aESD for AIN 3. All tested specimens were positive for HPV. Median duration of intervention was 56.1 min, one delayed postinterventional bleeding occurred, and specimen size was 12.05 cm. Median follow-up was 11.17 months. Three recurrences (20%) appeared: one was resected via biopsy and two were again treated with aESD. There was no progression to invasive anal cancer in the follow-up period.
CONCLUSIONS
Anal endoscopic submucosal dissection seems to be a safe and feasible treatment for AIN. Recurrences are seldom and can be treated again with the same method. Nevertheless, indications for resection in comparison to radiofrequency ablation, pharmacological therapy, and watch-and-wait strategy are still unclear.
TRIAL REGISTRATION
Ethics commission of Salzburg, Austria, EK-Nr. 1056/2023. Keywords: Endoscopic submucosal dissection, anal intraepithelial neoplasia, anal cancer.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Endoscopic Mucosal Resection; Papillomavirus Infections; Retrospective Studies; Feasibility Studies; Carcinoma in Situ; Anus Neoplasms
PubMed: 38102514
DOI: 10.1007/s10151-023-02896-x