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Purpose Treatment of invasive rectal adenocarcinoma is stratified into upfront surgery versus neoadjuvant chemoradiotherapy, in part, based on tumor distance from the anal verge (AV). This study examines the correlation between tumor distance measurements (endoscopic and MRI) and relationship to the anterior peritoneal reflection (APR) on MRI. Methods A single-center retrospective study was performed at a tertiary center accredited by the National Accreditation Program for Rectal Cancer (NAPRC). 162 patients with invasive rectal cancer were seen between October of 2018 and April of 2022. Sensitivity and specificity were determined for MRI and endoscopic measurements in their ability to predict tumor location relative to the APR. Results 119 patients had tumors endoscopically and radiographically measured from the AV. Pelvic MRI characterized tumors as above (intraperitoneal) or at/straddles/below the APR (extraperitoneal). True positives were defined as extraperitoneal tumors 10cm. Endoscopy was 81.9% sensitive and 64.3% specific in predicting tumor location with respect to the APR. MRI was 86.7% sensitive and 92.9% specific. Utilizing a 12cm cutoff, sensitivity of both modalities increased (94.3%, 91.4%) but specificity decreased (50%, 64.3%). Conclusion For locally invasive rectal cancers, tumor position relative to the APR is an important factor in determining the role of neoadjuvant therapy. These results suggest endoscopic tumor measurements do not accurately predict tumor location relative to the APR, and may lead to incorrect treatment stratification. When the APR is not identified, MRI-reported tumor distance may be a better predictor of this relationship.

Rectal small cell carcinoma is a rare and aggressive cancer subtype for which a consensus of optimal treatment has not yet been reached. This cancer presents a difficult surgical problem, and thus, the mainstay of treatment tends to mirror that of small cell carcinoma of the lung (chemotherapy, radiation therapy, and immune modulators). This brief report highlights current treatment options available for this rare and difficult entity. There is a significant need for large-center clinical trials and prospective studies to help determine the best treatment regimen to effectively care for patients with small cell carcinoma of the rectum.

Multimodal pain management within enhanced recovery after surgery (ERAS) protocols is designed to decrease opioid use, promote mobilization, and decrease postoperative complications.To evaluate the role of intravenous (IV) versus oral (PO) acetaminophen within an established ERAS protocol in colorectal surgery.This was a retrospective observational study.This research took place within an established perioperative colorectal surgery protocol.A total of 91 consecutive elective colorectal resections performed according to an ERAS protocol using only IV acetaminophen (IV group) were compared with 84 consecutive resections performed using one dose of IV acetaminophen followed by subsequent administration of oral acetaminophen (PO group). Our multimodal pain management strategy also included transverse abdominis plane blocks, celecoxib, and ketorolac medications for both groups. Opioid requirements, maximum and average daily pain scores by the Visual Analog Scale, and postoperative outcomes were compared between groups.There were no differences in maximum or average pain scores on postoperative days 0-3 or at time of discharge between IV and PO groups. Compared with the IV acetaminophen only group, the PO group received significantly more perioperative opioids through 72 hours postoperatively (68.8 oral morphine equivalents [OME] IV group vs. 93.7 OME PO group; P0.0001), were more likely to require opioid patient-controlled analgesia (8.9% IV group vs. 46.4% PO group; P0.0001), and were more likely to experience postoperative nausea and vomiting (33.0% IV group vs. 48.8% PO group; P = 0.0449).Significant limitations include the studies' retrospective nature and that it was performed at a single institution.Restriction of IV acetaminophen within an ERAS protocol in colorectal surgery was associated with increased opioid use, greater need for opioid patient-controlled analgesia, and increased incidence of postoperative nausea and vomiting. IV acetaminophen may be superior to oral acetaminophen in the early postoperative setting.Perioperative pain management, enhanced recovery after surgery, acetaminophen, multimodal pain control, nonopioid.

Background Anastomotic strictures represent a major source of morbidity in colorectal surgery with an incidence reported up to 30%. Despite this, the mechanism by which strictures develop remains unclear. This study aims to determine the incidence of colorectal anastomotic strictures and associated risk factors among a series of diverted patients. Materials and Methods A retrospective chart review was conducted of 142 patients over a 7-year period at a single institution after colorectal resection with anastomosis and diverting ileostomy creation re-examined with postoperative endoscopy. One patient was removed due to anastomotic tumor recurrence. Patient and technical factors were examined for significance using chi-square analysis. Logistic regression was used to perform multivariate analysis to estimate odds ratio (OR) and 95% confidence intervals (CI). Results Among 141 patients, 14.1% (20 patients) developed strictures detected on endoscopy. Strictures were observed in a greater percentage of women than men (21.2% vs 8%, P = .025). 30.6% of patients who underwent resections for diverticulitis developed strictures while those with neoplastic lesions and other indications had stricture rates of 6.8% and 17.6%, respectively ( P = .002). Anastomoses performed during a colostomy reversal were associated with a higher stricture rate (OR 4.23, 95% CI 1.37-13.40, P = .012). Anastomoses performed with a 28/29 mm EEA circular stapler demonstrated a significantly higher stricture rate versus a 31/33 mm stapler (OR 7.21, 95% CI 1.23-155.58, P = .045). Discussion Our data reveal that female sex, history of diverticulitis, anastomoses performed in the setting of colostomy reversal, and smaller stapler size are associated with a higher rate of anastomotic stricture.

Fluid management within Enhanced Recovery After Surgery (ERAS) protocols is designed to maintain a euvolemic state avoiding the negative sequelae of hypervolemia or hypovolemia. We sought to determine the effect of a recent ERAS protocol implementation on kidney function and on the incidence of postoperative acute kidney injury (AKI). A total of 132 elective colorectal resections performed using our ERAS protocol were compared to a propensity-matched group prior to ERAS implementation. Fluid balance, urine output, creatinine, and blood urea nitrogen (BUN) were recorded for all patients, and the incidence of AKI was determined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Implementation of our ERAS protocol decreased average postoperative length of hospital stay (5.5 vs 7.7 days, p

Lynch syndrome (LS) is a hereditary condition that increases one’s risk of developing colorectal, endometrial, and other extracolonic cancers. MD Anderson Cancer Center at Cooper implemented a reflex screening protocol for DNA mismatch repair (dMMR) deficiency. Those with findings suspicious for LS were referred for genetic counseling (GC). Our goal was to assess compliance with GC and factors associated with successful follow-up. Immunohistochemistry (IHC) for the MMR proteins MSH2, MLH1, MSH6, and PMS2 was performed on all colorectal tumor resections from patients ≤70 years old and all stage II cancers. Tumors with loss of MLH1/PMS2 were subsequently tested for BRAF mutation or MLH1 promoter methylation to identify tumors with likely epigenetic inactivation of MLH1. Patients with loss of MLH1/PMS2 without BRAF mutations or with absence of MLH1 promoter methylation and those with loss of MSH2/MSH6 were referred to GC. Compliance with GC was assessed. Between March 2014 and August 2016, 203 tumors were tested by IHC. Fifteen (7.4%) patients had abnormal MMR protein expression patterns in the absence of BRAF mutation or MLH1 promoter methylation suggestive of possible LS. GC compliance was 35.7% overall and 85.7% in those with family history of LS-associated cancers. Overall, GC compliance was relatively low in our study. Interestingly, patients with a strong family history of LS-associated neoplasms were more likely to pursue GC. In the future, assessing and addressing barriers to seeking GC will provide opportunities to improve patient care through increased identification of patients with cancer predisposition syndromes.

Recent advances in molecular genetics and biotechnology will revolutionize the practice of medicine and surgery during the next decade. Surgeons must understand and begin to use the new technologies in the study of surgical biology and patient care. A brief overview of the principles of gene transfer and how this technology is used for treating metabolic disease is presented. Two examples of how recombinant viruses (vectors) can be used to study fundamental biology in the liver and pancreas are given. Familial hypercholesterolemia is used as a paradigm for a clinical gene transfer study and underscores the importance of surgeons in the development of novel therapeutic strategies.

The etiology and pathogenesis of inflammatory bowel disease (IBD) remains an area under intense investigation. Cytokine secretion, which is important in the regulation of normal gastrointestinal immune responses, appears to be dysregulated in IBD. In Crohn's disease, there appears to be an excessive T(H)1 T-cell response to an antigenic stimulus, leading to increased levels of proinflammatory cytokines, such as interferon-gamma (IFN-gamma), interleukin (IL)-12, IL-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In ulcerative colitis, a T(H)2 T-cell response appears to be the pathological process responsible for the inflammatory disease. New and innovative therapeutic strategies targeting cytokines, such as TNF-alpha, are producing some promising results in animal and human studies. As more is learned about the complex cytokine interactions in IBD, more effective treatments will undoubtedly ensue.

Mutations in the glucokinase (GK) gene cause type-2 maturity-onset diabetes of the young type 2 (MODY-2) and GK-linked hyperinsulinaemia (GK-HI). Recombinant adenoviruses expressing the human wild-type islet GK or one of four mutant forms of GK, (the MODY-2 mutants E70K, E300K and V203A and the GK-HI mutant V455M) were transduced into glucose-responsive insulin-secreting β-HC9 cells and tested functionally in order to initiate the first analysis in vivoof recombinant wild-type and mutant human islet GK. Kinetic analysis of wild-type human GK showed that the glucose S0.5 and Hill coefficient were similar to previously published data in vitro (S0.5 is the glucose level at the half-maximal rate). E70K had half the glucose affinity of wild-type, but similar enzyme activity. V203A demonstrated decreased catalytic activity and an 8-fold increase in glucose S0.5 when compared with wild-type human islet GK. E300K had a glucose S0.5 similar to wild-type but a 10-fold reduction in enzyme activity. E300K mRNA levels were comparable with wild-type GK mRNA levels, but Western-blot analyses demonstrated markedly reduced levels of immunologically detectable protein, consistent with an instability mutation. V455M was just as active as wild-type GK, but with a markedly reduced S0.5. The effects of the different GK mutants on glucose-stimulated insulin release support the kinetic and expression data. These experiments show the utility of a combined genetic, biochemical and cell-biological approach to the quantification of functional and structural changes of human GK that result from MODY-2 and GK-HI mutations.

Background/Purpose: Clinical application of gene therapy for patients who have inflammatory bowel disease or short bowel syndrome will require the development of new strategies to improve the efficiency of small intestinal gene transfer. Previously, the authors developed a method for adenoviral-mediated small intestinal gene transfer in vivo in neonatal and adult mice. The present study evaluates the hypothesis that the integrins α v β 3 and α v β 5 , the secondary receptors for adenoviral internalization, play a facilitative role in neonatal murine adenoviral-mediated small intestinal gene transfer. Methods: Immunohistochemical techniques identified the integrin α v β 3 and the integrin subcomponents α v , β 3 , and β 5 in neonatal and adult small intestine. The effects of integrin receptor antagonists on transgene expression was also studied in our neonatal model of adenoviral-mediated small intestinal gene transfer in vivo. Results: Gene transfer was significantly decreased by the addition of integrin receptor antagonists versus control peptide. Integrin α v β 3 and integrin subcomponent α v , β 3 , and β 5 are expressed in neonatal and adult small intestine. Integrin antagonists administered simultaneously blocked efficient adenoviral-mediated neonatal small intestinal gene transfer in vivo compared with control peptide. Conclusion: Strategies to upregulate integrin expression may improve adenoviral-mediated small intestinal gene transfer.

Recombinant adenovirus accomplishes highly efficient gene transfer in vivo. Adenoviral vectors would be more attractive vehicles for gene therapy if transgene expression was inducible and restricted to the target tissue. In these studies, we hypothesized that selective transgene expression of a recombinant adenovirus could be accomplished by using a tissue-specific promoter of transcription. A replication-defective adenoviral vector was engineered to express the lacZ marker gene under control of the murine pancreatic amylase promoter. Expression of this vector occurred exclusively in the pancreas in neonatal and adult mice, while a similar vector with a constitutive promoter accomplished transgene expression in several organs. Within the adenoviral construct, the amylase promoter retained its ability to be induced by dexamethasone and insulin. This model will serve as a paradigm for selective and inducible adenoviral transgene expression.

Gene transfer technology may provide a novel approach to treatment for pancreatic diseases. Recombinant adenovirus achieves efficient gene transfer in vivo. In this study, a murine model of adenoviral-mediated pancreatic gene transfer was developed, and the factors responsible for adenoviral elimination were investigated. Three days after direct pancreatic injection of a replication-defective adenovirus containing the lacZ transgene, a high proportion (76.8 +/- 6.7%) of pancreatic cells expressed beta-galactosidase, the gene product. Gene expression was absent by 28 days posttransduction. In immunodeficient mice, beta-galactosidase expression persisted with 20.0 +/- 6.0% of pancreatic cells staining positive 60 days after viral transduction. To test whether early viral proteins are the antigenic components responsible for the potent antiviral immune response, normal mice were injected with different adenoviral vectors containing early gene deletions. Vectors containing deletions in early region 2 or 4 expressed beta-galactosidase at 28 days. Presently available adenoviral vectors engineered to avoid this response offer minimal improvements in transgene duration. Further vector modifications or alternative strategies are needed to achieve stable pancreatic adenoviral transgene expression.

Pancreatic adenoviral gene transfer can be achieved with high efficiency; however, questions concerning tissue injury from this commonly used vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluated. Direct pancreatic injection with an adenoviral vector containing the Escherichia coli beta-galactosidase (beta-Gal; lacZ) transgene (H5.010CBlacZ) resulted in a high level of transgene expression (64 +/- 6% of pancreatic cells expressed beta-Gal) at 3 days following infection. However, amylase levels in four of five different subcellular pancreatic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated adenovirus did not have this effect, whereas both transduction with an adenoviral vector containing a different transgene and transduction with a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-transduction, and then returned to baseline at 21 days post-transduction. There was associated histologic damage (increased edema, inflammation, cell destruction, and vacuolization) at 3 and 7 days post-transduction, which resolved by 21 days. In summary, adenoviral transduction of the pancreas results in increased viral transgene expression and a uniform decrease in host amylase production throughout the pancreas. The normalization of amylase levels and histology suggest that organ recovery occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasible but will benefit from continued approaches to limit toxicity.

The authors sought to assess the feasibility of in vivo gene transfer to the small intestine using recombinant adenovirus in neonatal and adult mice.H5.010CMVlacZ is a replication-defective, E1-deleted human type 5 adenovirus, which contains the lacZ gene under the control of a cytomegalovirus promoter and enhancer. The lacZ gene was used as a marker because its gene product, beta-galactosidase, is readily detected by X-gal histochemistry. Sixty neonatal (3 to 5 days old) and 45 adult (6 to 8 weeks old) C57BL/6 mice were investigated. Intestinal gene transfer was attempted with H5.010CMVlacZ by intraperitoneal (i.p.), intraluminal (IL), and intramural (i.m.) injection. Based on prior studies, the optimal dose of H5.010CMVlacZ was 1 x 10(8) plaque forming units (pfu/mL). Control animals received saline injections. Gene transfer on repeat administration of adenovirus has been shown to be prevented by neutralizing antibody. To determine if neonatal inoculation induced a humoral immune response, neonates (n = 5) that received i.p. injections were rechallenged with intravenous H5.010CMV alkphos, a similar adenoviral construct containing the alkaline phosphatase marker gene. Serum samples were analyzed by Western blot to detect the presence of adenoviral-specific antibody.Gene transfer to neonatal small intestine was successful by IL gastric (n = 8/10), IL jejunal (n = 9/10) and i.p. (n = 10/10) routes 2 days after injection. Macroscopic staining was present in 90% of standardized 2-cm small bowel segments. Transgene expression was identified in intestinal smooth muscle, serosa, and epithelium. Gene transfer to the adult small intestine was successful by IL jejunal (n = 4/5), i.m. (n = 5/5), and i.p. (n = 1/5) injection of adenoviruslacZ with focal staining (5% of 2-cm segments) in epithelium including crypts, muscle, and serosa. Three weeks after i.p. H5.010CMVlacZ in neonates, intravenous injection with H5.010CMValkphos resulted in hepatic transgene expression (n = 4/5) that was indistinguishable from a primary intravenous inoculation; persistent, lacZ expression was not detectable in the liver or intestine (n = 0/5). Western blot analysis detected adenoviral-specific antibodies after adult IM but not after neonatal i.p. injection. Furthermore, 3 weeks after neonatal i.p. injection repeat administration by the i.m. route was successful (n = 4/ 4).Gene transfer to neonatal and adult small intestine is feasible using recombinant adenovirus and is more efficient in neonates as indicated by increased surface area of marker gene expression, effectiveness of intraperitoneal delivery, and the ability to readminister recombinant adenovirus.

The purpose of this study was to determine the rate of cancer in a modern series of colorectal polyps. All pathology reports from colon and rectal polyps from 1999 to 2002 were reviewed. Reports of bowel resections, cancer-free polyps, and polyp-free mucosal biopsies were excluded. Polyps were grouped by size, and the rate of adenocarcinoma was determined. χ2 was used for analysis. A total of 4,443 polyps were found, of which 3,225 were adenomatous [2,883 (89.4%) tubular adenomas, 399 (9.3%) tubulo-villous adenomas, 32 (1.0%) villous adenomas, and 11 (0.3%) carcinomas]. The rate of adenocarcinoma by size was 0.07 per cent for polyps 2 cm, representing significantly fewer cancers for each category of polyp size than the accepted standard. The rate of carcinoma in colon polyps is much lower than previously thought and currently stated in many texts. These data do not alter the recommendations for polyp removal, however, failure to retrieve a specimen in a polyp

The purpose of this study was to determine the rate of cancer in a modern series of colorectal polyps. All pathology reports from colon and rectal polyps from 1999 to 2002 were reviewed. Reports of bowel resections, cancer-free polyps, and polyp-free mucosal biopsies were excluded. Polyps were grouped by size, and the rate of adenocarcinoma was determined. x2 was used for analysis. A total of 4,443 polyps were found, of which 3,225 were adenomatous [2,883 (89.4%) tubular adenomas, 399 (9.3%) tubulo-villous adenomas, 32 (1.0%) villous adenomas, and 11 (0.3%) carcinomas]. The rate of adenocarcinoma by size was 0.07 per cent for polyps1 cm, 2.41 per cent for polyps 1-2 cm, and 19.35 per cent for polyps2 cm, representing significantly fewer cancers for each category of polyp size than the accepted standard. The rate of carcinoma in colon polyps is much lower than previously thought and currently stated in many texts. These data do not alter the recommendations for polyp removal, however, failure to retrieve a specimen in a polyp1 cm in size is unlikely to have an adverse outcome because the chances of malignancy are very low.

or anorectal disease is a primary feature of Crohn’s disease, with a prevalence of 8% to go%, and typically is considered to afflict approximately one in three patients.36, 58, n, 78 It is seldom the only site of disease. The range of anorectal disease is great because of variability in the classification of perianal disease and in the caution exercised in the search for such lesions. Variation also occurs within subgroups of patients with Crohn’s disease. More than half of patients with colonic involvement will have anal complications, whereas in less than 20% of patients with small-bowel disease, anal symptoms are likely to develop.76 The prevalence of perianal disease also has been found to be greater in blacks than in CLINICAL PRESENTATION Most patients with Crohn’s disease present with abdominal pain, diarrhea, and weight loss, but 5% of patients with Crohn’s disease present with anal lesions only, and most will develop intestinal symptoms, sometimes many years later.67 The spectrum of anal complaints is

The pancreas is an ideal organ for adenoviral gene therapy because of the high level of gene transfer that can be achieved and because of the many diseases that can potentially be treated using this technology. In this report, we characterize the immune response to direct pancreatic injection of adenovirus and we overcome some of the limitations it imposes by using immunosuppression. Direct injection of recombinant adenovirus into the pancreas leads to the production of neutralizing antibodies and to sensitized splenocytes which engage in increased cytotoxic, lymphoproliferative, and cytokine release activity when reexposed to adenovirus. Transgene expression is transient and the vector cannot be readministered. Deletion of CD4+ T helper cells improves expression over time (40% of pancreatic cells express transgene at day 28 vs. 5% in controls), and allows the vector to be readministered in the pancreas, albeit, inefficiently, when compared to naive animals. Similarly, blockade of CD40 ligand, which preserves the CD4+ T helper cell population, also improves expression over time (30% of pancreatic cells express transgene at day 28), and allows the vector to be readministered. With both approaches, neutralizing antibodies are decreased and the remaining splenocytes do not engage in activated immune responses. Thus, local delivery of the adenoviral vector induces a systemic response that prevents pancreatic readministration, even with direct injection. Blockade of CD40 ligand and T helper cell depletion are transient regimens that induce systemic immunosuppression. Until the development of newer strategies that selectively suppress adenoviral immune responses, these are viable alternatives for enhancement of pancreatic adenoviral delivery.

Background This case report draws attention to the debated role of prophylactic oophorectomy in women undergoing definitive surgical resection of colon and rectal cancers. It can be challenging to discern the indications and appropriate patient population for this procedure based on the current literature. Potential benefits include treatment and prevention of metastatic disease, preventing development of primary ovarian cancer, and prolonging survival. Negative effects include an increase in operative time and potential morbidity, development of osteoporosis, the risk of cardiac events, and decreasing sexual function. Multiple patient factors such as age, menopausal status, patient preference, presence of hereditary conditions, exposure to radiation, site, and stage of disease should be considered. Case presentation We present a case in which a premenopausal 49-year-old female underwent a prophylactic bilateral salpingo-oophorectomy concurrently with a low anterior resection following neoadjuvant chemoradiation for clinical stage III rectal cancer. On pathologic examination, resection margins and all 14 lymph nodes harvested were negative for malignancy. Interestingly, she was found to have micrometastatic adenocarcinoma in the bilateral ovaries which had appeared grossly normal at the time of surgery. Conclusions After consideration of the current literature, patient preference, and our clinical judgment, our patient ultimately had a therapeutic effect after undergoing prophylactic bilateral oophorectomy concurrently with a low anterior resection for rectal cancer. The addition of prophylactic oophorectomy in a select population, specifically women 50 years of age or younger and/or women who are in the premenopausal state, may carry a survival benefit in the setting of definitive surgical resection of colon and rectal cancers.