NSQIP 5-factor modified frailty index and complications after ileal anal pouch anastomosis for ulcerative colitis.

Background: Frailty has been associated with worse postoperative outcomes. The 5-factor modified frailty index (mFI-5) is an objective measure although its validity in measuring frailty in patients undergoing ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (CUC) has not been reported. Methods: This study used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted proctectomy database. The mFI-5 was calculated by five preoperative diagnoses: insulin-dependent or noninsulin-dependent diabetes, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and dependent or partially dependent functional status. The impact of mFI-5 on minor and major postoperative morbidity in CUC patients undergoing IPAA was analyzed. Results: The cohort included 1454 patients (median age 38 years, median body mass index [BMI] 26 kg/m2) of which 87 % had a mFI-5 = 0, 11 % had a mFI-5 = 1, and 2.5 % a mFI-5 ≥ 2. In multivariable logistic regression, mFI-5 ≥ 2 was significantly associated with minor complications (OR = 2.29, 95 % CI [1.00-5.22], p = 0.049), but not with major complications (p = 0.860). Conclusion: IPAA for CUC is associated with high postoperative morbidity, however, the mFI-5 alone has limited utility in determining which patients are at a higher risk of complications due to frailty. These observations suggest there is a need for more relevant instruments to measure frailty in this patient cohort.

Equivalency of short-term perioperative outcomes after open, laparoscopic, and robotic ileal pouch anal anastomosis. Does procedure complexity override operative approach?

Background: Ileal pouch anal anastomosis is the treatment of choice for patients with chronic ulcerative colitis and familial adenomatous polyposis undergoing a proctocolectomy and desiring bowel continuity. It is a technically complex operation associated with significant morbidity and may be performed by an open, laparoscopic, or robotic approach. However, there is a paucity of data regarding the comparative perioperative outcomes between these 3 techniques outside of institutional studies. Methods: The NSQIP targeted proctectomy data set was used to identify patients who underwent open, laparoscopic, and robotic ileal pouch anal anastomosis between 2016 and 2019. Thirty-day outcomes between different surgical approaches were compared using univariate and multivariable analysis. Results: During the study period, 1,067 open, 971 laparoscopic, and 341 robotic ileal pouch anal anastomosis were performed. The most frequent indications were inflammatory bowel disease (64%), malignancy (18%), and familial adenomatous polyposis (7%). Mean age of the cohort was 43 ±â€¯15 years with 43% female and 76% with body mass index ≤ 30 kg/m2. Overall morbidity was 26.8% for the entire cohort with 4% anastomotic leak, 6% reoperation, 21% ileus, and 21% readmission rate. After adjusting for available confounders, operative approach was not associated with better short-term outcomes, including length of stay, overall morbidity, anastomotic leak, reoperation, incidence of ileus, and 30-day readmissions. Conclusion: Ileal pouch anal anastomosis continues to be associated with significant postoperative morbidity regardless of operative approach. Patient-related advantages in terms of perioperative outcomes for laparoscopic and robotic platforms compared to open surgery are less pronounced in complex operations such as ileal pouch anal anastomosis.

Surgical management of large, connected perineal and pelvic epidermal inclusion cysts mimicking a dumbbell-shaped lesion in an adult male.

INTRODUCTION AND IMPORTANCE: Epidermal inclusion cysts are a common benign finding, and they are predominantly asymptomatic. They can rarely form in the pelvis or abdomen, however, and may cause symptoms secondary to mass effect. This case highlights management of an anterectal epidermal inclusion cyst connected to the perineal cyst, mimicking a dumbbell-shaped lesion, found in a male. CASE PRESENTATION: This is a unique case of a 21-year-old Caucasian male with a palpable perineal mass, lower extremity hypoesthesia, and constipation who was found to have a complex-shaped cyst on computed tomography and magnetic resonance imaging. This was ultimately managed with a two-stage perineal and transabdominal resection. CLINICAL DISCUSSION: This case highlights that perineal epidermal inclusion cysts may have pelvic extension, especially in patients with additional new-onset neurologic, gastrointestinal, or urologic symptoms. These symptoms should completely resolve after resection. Additionally, resection is recommended to prevent complications including malignant degeneration and fistulization. CONCLUSION: This is the first reported case of an anterectal, epidermal inclusion cyst connected to a perineal cyst found in a male. Perineal and pelvic cysts may be synchronous and may be connected through the pudendal canal. These masses can be safely removed via a combined perineal and transabdominal resection. The connecting portion of lesions that have both pelvic and perineal components should be meticulously identified and dissected because even a thin, patent segment - if left unresected - may result in lesion recurrence.

AP-2α-Mediated Activation of E2F and EZH2 Drives Melanoma Metastasis.

In melanoma metastasis, the role of the AP-2α transcription factor, which is encoded by TFAP2A, is controversial as some findings have suggested tumor suppressor activity while other studies have shown high TFAP2A expression in node-positive melanoma associated with poor prognosis. Here we demonstrate that AP-2α facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathway including EZH2. A BioID screen found that AP-2α interacts with members of the nucleosome remodeling and deacetylase (NuRD) complex. Loss of AP-2α removed activating chromatin marks in the promoters of EZH2 and other E2F target genes through activation of the NuRD repression complex. In melanoma cells, treatment with tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage-independent colony formation and demonstrated heritable antimetastatic effects, which were dependent on AP-2α. Single-cell RNA sequencing analysis of a metastatic melanoma mouse model revealed hyperexpansion of Tfap2a High/E2F-activated cell populations in transformed melanoma relative to progenitor melanocyte stem cells. These findings demonstrate that melanoma metastasis is driven by the AP-2α/EZH2 pathway and suggest that AP-2α expression can be used as a biomarker to predict responsiveness to EZH2 inhibitors for the treatment of advanced melanomas. SIGNIFICANCE: AP-2α drives melanoma metastasis by upregulating E2F pathway genes including EZH2 through inhibition of the NuRD repression complex, serving as a biomarker to predict responsiveness to EZH2 inhibitors.

Staged Approaches to Restorative Proctocolectomy with Ileoanal Pouch-When and Why?

Restorative proctocolectomy (RPC) with ileal pouch anal-anastomosis (IPAA) is commonly performed for patients with ulcerative colitis, familial adenomatous polyposis, and selected phenotypes of Crohn's disease (CD). Due to concerns about the effects of surgical complications on pouch functional outcomes, debate remains surrounding when and whether RPC with IPAA should be performed in a staged manner. Particularly debated are the timings of the IPAA, whether it is constructed at time of the proctocolectomy and whether to utilize temporary fecal diversion with a loop ileostomy. RPC with IPAA can be performed in one, two, or three stages, with each stage typically separated by 3-6 months. Proponents of a staged approach argue that poor pouch function, which is often a result of IPAA complications, including leak and infection, can be difficult to overcome and mandate additional, major surgeries, and that staging pouch creation and pairing with a protective ileostomy reduce those complications. However, subjecting patients to multiple surgeries and prolonging their time with an ileostomy present unique risks as well. Surgeons' experience and preference and patient characteristics need to be considered when determining operative planning. Highly selected patients with CD can be considered for RPC with IPAA, although with an acknowledgment of inherently higher pouch failure rates. Understanding the short- and long-term consequences of RPC with IPAA construction can help surgeons determine the appropriate approach.

Intra-abdominal and Anorectal Abscesses.

Intra-abdominal and anorectal abscesses are common pathologies seen in both inpatient and outpatient settings. To decrease morbidity and mortality, early diagnosis and treatment are essential. After adequate drainage via a percutaneous or incisional approach, patients need to be monitored for worsening symptoms or recurrence and evaluated for the underlying condition that may have contributed to abscess formation.

AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer.

Activating protein 2 alpha (AP-2α; encoded by TFAP2A) functions as a tumor suppressor and influences response to therapy in several cancer types. We aimed to characterize regulation of the transcriptome by AP-2α in colon cancer. CRISPR-Cas9 and short hairpin RNA were used to eliminate TFAP2A expression in HCT116 and a panel of colon cancer cell lines. AP-2α target genes were identified with RNA sequencing and chromatin immunoprecipitation sequencing. Effects on cell cycle were characterized in cells synchronized with aphidicolin and analyzed by FACS and Premo FUCCI. Effects on invasion and tumorigenesis were determined by invasion assay, growth of xenografts, and phosphorylated histone H3 (PHH3). Knockout of TFAP2A induced significant alterations in the transcriptome including repression of TGM2, identified as a primary gene target of AP-2α. Loss of AP-2α delayed progression through S-phase into G2-M and decreased phosphorylation of AKT, effects that were mediated through regulation of TGM2. Buparlisib (BKM120) repressed in vitro invasiveness of HCT116 and a panel of colon cancer cell lines; however, loss of AP-2α induced resistance to buparlisib. Similarly, buparlisib repressed PHH3 and growth of tumor xenografts and increased overall survival of tumor-bearing mice, whereas, loss of AP-2α induced resistance to the effect of PI3K inhibition. Loss of AP-2α in colon cancer leads to prolonged S-phase through altered activation of AKT leading to resistance to the PI3K inhibitor, Buparlisib. The findings demonstrate an important role for AP-2α in regulating progression through the cell cycle and indicates that AP-2α is a marker for response to PI3K inhibitors. IMPLICATIONS: AP-2α regulated cell cycle through the PI3K cascade and activation of AKT mediated through TGM2. AP-2α induced sensitivity to Buparlisib/BKM120, indicating that AP-2α is a biomarker predictive of response to PI3K inhibitors.

AP-2γ Is Required for Maintenance of Multipotent Mammary Stem Cells.

Mammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Here, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors. AP-2γ regulated the expression of genes known to be required for mammary development, including Cebpb, Nfkbia, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ can regulate development of mammary gland structures potentially regulating maintenance and differentiation of multipotent MaSCs.