The two-year rodent carcinogenicity bioassay, often using the subcutaneous (SC) route for parenterally administered drugs, is a regulatory standard for evaluating carcinogenic potential. However, repeated SC injections of nongenotoxic agents or implantation of inert materials frequently induce injection-site sarcomas in rodents due to a species-specific response to chronic inflammation. This contrasts with humans, who rarely develop such tumors at injection sites, highlighting the limited relevance of these rodent findings for human risk. Extensive literature documents that rodents are uniquely susceptible to developing injection-site sarcomas following chronic local irritation and exaggerated fibroblastic proliferation responses. Marketed drugs, including pegvisomant and insulin glargine, have caused injection-site sarcomas in rodent studies but pose no corresponding risk to humans. These findings are noted in drug labeling but do not restrict marketing. Given the species-specific nature of this phenomenon and the practical challenges of dosing in long-term rodent studies, SC route of administration should be avoided for rodent carcinogenicity studies whenever feasible.

Mass Spectrometry Imaging (MSI) is a powerful tool to understand molecular pathophysiology and therapeutic and toxicity mechanisms, as well as for patient stratification and precision medicine. MSI, a label-free technique offering detailed spatial information on a large number of molecules in different tissues, encompasses various techniques including Matrix-Assisted Laser Desorption Ionization (MALDI), Desorption Electrospray Ionization (DESI), and Secondary Ion Mass Spectrometry (SIMS) that can be applied in diagnostic and toxicologic pathology. Given the utmost importance of high-quality samples, pathologists play a pivotal role in providing comprehensive pathobiology and histopathology knowledge, as well as information on tissue sampling, orientation, morphology, endogenous biomarkers, and pathogenesis, which are crucial for the correct interpretation of targeted experiments. This article introduces MSI and its fundamentals, and reports on case examples, determining the best suited technology to address research questions. High-level principles and characteristics of the most used modalities for spatial metabolomics, lipidomics and proteomics, sensitivity and specific requirements for sample procurement and preparation are discussed. MSI applications for projects focused on drug metabolism, nonclinical safety assessment, and pharmacokinetics/pharmacodynamics and various diagnostic pathology cases from nonclinical and clinical settings are showcased.

Introduction: Although endoscopic balloon dilation has been the mainstay management of benign colorectal anastomotic strictures, novel techniques such as endoscopic stricturotomy or stricturoplasty (defined as stricturotomy with clip placement) have been increasingly employed by advanced endoscopists based on their expertise. We describe a novel technique of stricturotomy followed by AXIOS stent placement in the same setting for a tight short segment ileorectal anastomotic stricture in a patient with MUTYH associated polyposis (MAP). Case Description/Methods: A 61 yo M with MAP managed with subtotal colectomy and ileorectal anastomosis was found to have asymptomatic anastomotic stricture noted on surveillance colonoscopy which was unable to be traversed with a pediatric colonoscope. Balloon dilation to 15 mm was performed. A year later the patient presented with vomiting and abdominal distension and with imaging evidence of distended small bowel. Colonoscopy showed a tight anastomotic stricture (1 cm in length and 3 mm in diameter). Endoscopic stricturotomy was performed in a circumferential fashion using an IT nano 2 knife with electrocautery, followed by the placement of an AXIOS stent (10 mm x 20 mm). There were no major complications. At one month follow up, the patient had complete resolution of his symptoms and is planned for stent removal. (Figure) Discussion: Endoscopic balloon dilation is the most common form of management of benign colorectal strictures with restenosis observed in about 11% of cases. Novel advanced endoscopic techniques such as stricturotomy or stricturoplasty have been performed predominantly for IBD related anastomotic strictures with comparable efficacy to surgical resection. The combination of stricturotomy followed by stent placement in the same setting is novel, and can be considered to maintain lumen patency for tight strictures to achieve durable response. Major complications during stricturotomy include bleeding that ranges from 3-14%. This complication can easily be treated using soft coagulation setting with the endoknife, coagulation grasper forceps, and other simple tamponade techniques. Risk of perforation is very rare. In summary, we describe a novel endoscopic technique for the treatment of benign colorectal anastomotic strictures which may result in more durable patency. Further studies are needed to assess long term outcomes.Figure 1.: Endoscopic view of illiorectal anastomotic stricture (A) traversed with IT nano 2 knife (B) followed by AXIOS stent placement (C).

Introduction: Small intestinal strictures that are distal to the duodenum, particularly the jejunum, are uniquely complicated to manage. Adult endoscopes are often too short or too rigid to reach this region of the small bowel. Furthermore, duodenal stents are not flexible enough and are uncovered. In this case, we were able to place several esophageal stents in the proximal jejunum using a pediatric colonoscope that could not be placed previously. Case Description/Methods: A 56 year-old woman with hypertension, obstructive lung disease, and a prior ischemic stroke presented to the hospital for four days of postprandial emesis, abdominal distention, epigastric pain, and constipation. She previously underwent appendectomy and hysterectomy, and had no prior endoscopic studies. Computed tomography (CT) was performed demonstrating mural thickening of the distal duodenum and partial occlusion of the small bowel with regional lymphadenopathy, and a large left adrenal mass. Esophagogastroduodenoscopy (EGD) showed an intrinsic severe stenosis in the distal duodenum. After biopsies were taken, the tissue was found to be a primitive neuroectodermal tumor. Because of the presence of mesenteric adhesion and extensive stenosis, it was decided to correct the stricture endoscopically rather than with surgical intervention. Using a pediatric colonoscope and fluoroscopic guidance, three stents were placed sequentially and telescoping each other from the proximal jejunum to the distal duodenum: a fully covered 20 mm x 120 mm esophageal stent, a partially covered 18 mm x 97 mm esophageal stent, and a fully covered 20 mm x 60 mm esophageal stent (Figure). There were no immediate complications with the procedure and repeat imaging demonstrated luminal patency. Due to the expansion of the stents through a tight stricture, the abdominal pain and pressure was present despite no evidence of perforation on CT. Discussion: This demonstrates the feasibility of utilizing multiple esophageal stents to help relieve more distal gastrointestinal obstructions that were not feasible in the past. The covered esophageal stents are extremely useful when there is discontinuity in the lumen of the small bowel to keep the natural flow of food and help prevent surgical interventions. Watch the video at https://tinyurl.com/ACGAbstractS352Figure 1.: (A) Coronal CT image of a large abdominal mass involving loops of bowel and jejunum. (B) Abdominal x-ray showing interval placement of stents from the distal duodenum to the proximal jejunum.

Sarcomatoid tumors are very rare biphasic tumors characterized by a mixture of malignant epithelial and mesenchymal cells that have been usually identified in the lungs with other documented cases in skin, bone, thyroid gland, salivary glands, breast, and genitourinary and gastrointestinal systems. They have an incidence estimated to be 0.5 to 0.8 per 100 000 per year. Three classic features include the presence of a genuine sarcomatous component, no transitional zone between carcinomatous and sarcomatous components, and immunohistochemistry of the sarcomatous component that is positive for mesenchymal markers and negative for epithelial markers. Sarcomatoid carcinoma of the gastrointestinal tract is rare but more commonly found within the stomach, gallbladder, and esophagus. Small bowel involvement is very rare.

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article-related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist's experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

Introduction: Abdominal lymphangioma is a rare finding. Most of them arise from the mesentery or omentum, and those arising from the GI tract is extremely rare. Lymphangioma involving the colon is usually asymptomatic and can be encountered during screening colonoscopy. It is characterized by a soft, cystic appearing lesion that contains dilated lymphatic channels. Cecal lesions should be differentiated from appendiceal neoplasms including mucocele and carcinoid tumors. Case Description/Methods: A 61-year-old male underwent a screening colonoscopy which revealed a soft cystic lesion in the cecum measuring about 20 mm wide, with a positive cushion sign. Appendiceal orifice and the ileocecal valve appeared normal. CT of the abdomen showed a low-density cystic lesion arising from the wall of the cecum and separate from the appendix. Endoscopic ultrasound (EUS) exam using a mini ultrasound probe revealed a cystic anechoic subepithelial lesion measuring (18 x 17 mm) with septations arising from the submucosa (Figure). Discussion: Lymphangioma of the colon is a rare asymptomatic finding often encountered during screening colonoscopy. It is characterized by a soft, cystic appearing lesion that contains dilated lymphatic channels. It is often solitary and is usually benign in nature. Cecal lesions, especially if in proximity to the appendiceal orifice should be differentiated from appendiceal neoplasms including mucocele and carcinoid tumors. Lymphangioma may be difficult to be differentiated from a lipoma on endoscopic appearance. Signal characteristics on CT imaging differ between the 2; Lipomas have characteristics similar to subcutaneous fat and usually have Hounsfield unit measurements between -65 and -120; Lymphangiomas on the other hand are cystic appearing with Hounsefield units corresponding to the fluid density and the average Hounsefield unit of the lesion in our patient was 17. Similarly, endosonographic features vary between the 2. Lipomas are hyperechoic lesions arising from the submucosa, whereas lymphangiomas are anechoic. Endoscopic appearance of a cystic lesion often with a bluish hue and a positive cushion/ pillow sign and ultrasonographic features (anechoic subepithelial lesion often with septations and without solid component) aid towards the diagnosis of lymphangioma without the need for invasive tissue diagnosis. Rare cases of intussusception from large cecal lymphangioma have been reported. Given the benignity, surgical intervention is not needed in asymptomatic patients.Figure 1.: positive cushion sign.

Introduction: Frontline therapy for Ulcerative colitis (UC) includes mesalamine. It is usually well tolerated with minor side effects. We present a rare case of mesalamine induced myocarditis in a patient with Ulcerative colitis within a week of starting the medication. Case description/methods: A 53 year old female with past medical history of left sided Ulcerative colitis (UC) recently started on mesalamine presented with vomiting, diarrhea, and chest pain for 3 days. She was found to be borderline hypotensive, tachycardic and febrile to 102.4. Physical exam was notable for mild LLQ pain without rebound tenderness. Labs revealed elevated troponin of 14, Hb of 10 and without leukocytosis or elevated lactate. C. Difficile stool toxin was positive. EKG revealed sinus tachycardia without ischemic changes. CTA ruled out PE and aortic dissection, but revealed mild cardiomegaly with minimal pericardial effusion (Figure 1). Echocardiogram showed diffuse hypokinesis and moderately reduced LV systolic function with EF of 40%. She was admitted to the cardiac care unit and cardiac catheterization demonstrated normal coronaries. Mesalamine was discontinued resulting in normalization of troponin and clinical improvement. Repeat echocardiogram a few weeks after stopping mesalamine showed normalization of EF. Discussion: Cardiac complications seen in inflammatory bowel disease either as extraintestinal manifestations or secondary to drug induced side effects are rare, but serious occurrences with delayed diagnosis could be catastrophic. Mesalamine induced myocarditis can occur within the first week of treatment or even years after. The pathophysiology of this process has not been clearly identified, but is thought to be related to hypersensitivity to the drug considering discontinuation leads to improvement in cardiac function as seen with our patient. Confounding factors in this presentation include sepsis/viral etiologies, coexisting CAD or very rarely extraintestinal manifestation of IBD itself. Our patient was initially thought to have septic shock from C. Difficile infection, but further cardiac workup revealed abnormalities not explained by infection alone. The temporal association, normal coronaries and reversal of cardiomyopathy post discontinuation of mesalamine further points towards the association. This case highlights the importance of considering drug induced myocarditis in a patient on mesalamine with cardiac symptoms where prompt diagnosis and drug withdrawal can reverse cardiomyopathy with good prognosis.Figure 1.: Mild cardiomegaly, LVH, and minimal pericardial effusion.

Introduction: Sarcomatoid tumors are rare biphasic tumors characterized by a mixture of malignant epithelial and mesenchymal cells that are usually identified in the lungs. In some instances, the tumors can also be found in the skin, bone, breast, GU tract, GI tract (GIT), thyroid gland, and salivary glands. When found in the small intestine, they have an incidence estimated to be 0.5 - 0.8 per 100,000 per year. Case Description/Methods: A 61-year-old male presented with complaints of non-specific abdominal pain and unintentional weight loss of 30 lbs. Labs revealed normocytic anemia with a hemoglobin of 9.5. CT of the abdomen and pelvis demonstrated a 7.8 x 7.0 x 7.1 cm irregular, a heterogeneous mass contiguous with the duodenum, gastric antrum, and pancreas. Esophagogastroduodenoscopy revealed an edematous pylorus with a medium-sized fungating, polypoid, and ulcerated mass in the anterior wall of the duodenal bulb. Specimens were taken and underwent immunohistochemical staining. Findings were positive for s100 and negative for MCK, CD117, CD34, and SMA; The spindle cells were focally positive for EMA and negative for AE1/AE3, CAM5.2, and sox10. The final pathologic diagnosis was sarcomatoid carcinoma with osteoclast-like giant cells. Discussion: 3 unique features of sarcomatoid tumors include the presence of a genuine sarcomatous component, no transitional zone between carcinomatous and sarcomatous components, and immunohistochemistry of the sarcomatous component that is positive for mesenchymal markers and negative for epithelial markers. Sarcomatoid carcinoma of the GIT is rare, typically occurring in the stomach, gallbladder, or esophagus. It affects males more than females. The average age of diagnosis is 57 years old. Risk factors have not yet been established. The tumor tends to have an aggressive clinical course with an overall 5-year survival rate of about 20%. Immunohistochemistry is necessary for diagnosis as small intestine tumors have only minor histological differences. Immunohistochemical studies of the tumor show pleomorphic cells positive for cytokeratin AE1/AE3, CAM 5.2, and vimentin and negative for desmin, muscle-specific actin, CD34, DOG1, c-kit, and S-100. The only treatment is surgery with wide excision. Monoclonal antibodies against programmed death protein (PD-1) and its ligand, PD-L1, have promising antitumor activity in several other malignancies and may represent possible future non-surgical treatment options for this tumor.

Introduction: Gastrointestinal follicular lymphoma (FL) is a rare, but distinct extra-nodal variant of non-Hodgkin’s lymphoma. Its incidence has grown outside of known genetic inheritance, due to epigenetic mutations from increased toxic exposure to benzene and pesticides, expanded life spans, and widespread standardized screening efforts. Diagnosis is by colonoscopy-obtained tissue staining and can be missed if alternative CRC screening methods are used in lieu. Case Description/Methods: A 54-year-old Ukranian male with a past medical history of HTN and GERD came in for an asymptomatic screening colonoscopy. One 8 mm polyp in the transverse colon was positive for FL. IHC staining demonstrated atypical small B-lymphocytes, positive for CD45+, CD20+, PAX5+, CD10+, and BCL-2+. Bloodwork, including LDH, beta-2-microglobulin, were normal. A staging PET scan was negative indicating an isolated disease within the colonic polyp. As the patient was asymptomatic, no further treatment was indicated and the patient was scheduled for regular follow-up. Discussion: GI FL is a B-cell lymphoma with an incidence slightly higher in women and a median age of 65. Occurrence outside of the bone marrow, spleen, or liver is uncommon. Descending incidence within the GI tract is the duodenum, ileum, stomach, and rarely colon. Within the colon, it presents asymptomatically. Definitive diagnosis is by a colonoscopy-obtained tissue staining. Colonoscopy adherence is generally high after the age of 65, given the median age of colorectal cancer incidence is 67 and the availability of Medicare coverage. However, if alternatively approved screening modalities are utilized such as the gFOBT, FIT, FIT-DNA, or flexible sigmoidoscopy, then the diagnosis of a FL might be missed until either mass or metastatic effects become apparent. Diagnostic work-up includes IHC staining for CD-20, CD-36, a follicular cell pattern, increase in B cells, bcl-2, bcl-6, and a 14:18 translocation by FISH or PCR (85% of cases). Investigation into a primary NHL, leukemia, or MDS includes flow cytometry, bone marrow biopsy, and cytogenetics. Increased LDH indicates rapid progression with staging done by PET or pan CTs. Colonic FL have a 10-year survival rate of 80% and an indolent course, so treatment is only indicated if the patient is symptomatic. Treatment for stage 1 is radiation, stages 2-4 is CHO P-R chemotherapy. Adjuvant or refractory treatments include anti-CD20 monoclonal antibodies, such as rituximab or obinutuzumab.Figure 1.: A. 8mm semi pedunculated polyp in the transverse colon. B. Polyp site post hot snare removal C. Colonic mucosa with nodular infiltrate of atypical small b lymphocytes; predominantly with centrocyte-like morphology.

Introduction: A transcatheter aortic valve replacement (TAVR) carries a 2% risk of postoperative upper gastrointestinal bleeding. It presents as extensive bleeding resulting in hemorrhagic shock or respiratory failure. In this case, an early clot with sentinel bleeding prevented the widening of a full thickness aortoesophageal fistula formed from the TAVR placement, was symptomatic enough to prompt an earlier esophagogastroduodenoscopy (EGD) and prevented a probable fatality. Case Description/Methods: An 85-year-old male with a past medical history of AAA repair, GERD, HLD, TIA, aortic dissection s/p coronary bypass graft, AS with TAVR 5 months prior presented with hematemesis after initiating colonoscopy bowel prep. He also had unintentional 30-lb weight loss over 3 months, fecal incontinence, and melena. Medications include a daily aspirin. Abdominal CT demonstrated an 8cm aortic arch aneurysm, a 5cm descending thoracic aortic aneurysm, and a 5.8 x 4 cm collection posterolateral to the aorta with proximal dilation of the esophagus. EGD demonstrated a partially obstructing protruding mass in the esophagus 20 cm from the incisors with sentinel bleeding from an adherent clot. The mass was determined to be extrinsic compression from the aortic arch aneurysm with the TAVR seen through the aortoesophageal fistula (Image 1A-1B). The stomach and duodenum were unremarkable. Patient was transferred to vascular surgery where a 1cm compressed Amplatzer Vascular Plug II embolization and reinforcement of the endoleak was done. Patient remained hemodynamically stable and discharged home with a vascular follow up. Discussion: Aorto-esophageal fistula following TAVR is a rare complication with a wide etiology ranging from infections, antithrombotic use, pressure necrosis, angiodysplasia, underlying PUD, or uncontrolled comorbidities such as HTN. Our patient’s risk factors were his elderly age, comorbidities, use of daily aspirin, and contribution from the pressure or ischemic necrosis of the aortic aneurysm compressing on the esophagus. Presentation involves hemoptysis, chest pain, hemorrhagic shock, respiratory failure and frank bleeding. CTA is considered the initial test of diagnosis as endoscopy, though sensitive, could rupture the clot and unleash massive bleeding. In this case, sentinel bleeding and visualization of the TAVR through the fistula was enough to diagnose and retreat to be treated appropriately with embolization and reinforcement.Figure 1.: Esophageal mass with pathology.

Introduction: Gastric mucosal calcinosis (GMC) is a rare histological finding characterized by calcium deposition in the gastric mucosa. It has been linked to electrolyte abnormalities in the setting of malignancy, chronic renal failure, and hyperparathyroidism. It can lead to long-standing dyspepsia. Case Description/Methods: A 61-year-old man presented with 2 weeks of sharp epigastric pain. He reported multiple hospitalizations in the past for similar symptoms. His medical history was significant for ESRD secondary to hypertension requiring hemodialysis as well as renal osteodystrophy secondary to hyperparathyroidism resulting in a parathyroidectomy. Labs revealed a hemoglobin of 10.5 mg/dL, an elevated BUN 35 mg/dL, a creatinine of 8 mg/dl and hypercalcemia with a Ca level of 11.5 mg/dl. The evaluation included an esophagogastroduodenoscopy (EGD), a colonoscopy, and a CT angiogram of the abdomen. The CT of the abdomen revealed diffuse atherosclerotic disease with calcium deposition in the soft tissue and vasculature with no evidence of acute pathology. Colonoscopy discovered pan-diverticulosis. The EGD showed evidence of severe gastritis. Pathology of the stomach biopsies demonstrated numerous black calcium deposits within the squamous mucosa and fibrinopurulent exudate significant for gastric mucosal calcinosis. Discussion: Mucosal calcinosis has a predisposition to gastric, cardiac, lung, and kidney tissue due to their intracellular alkalinity. GMC is categorized into dystrophic, idiopathic, and metastatic. Metastatic calcifications occur in the settings of altered metabolism of serum calcium and phosphorus and can occur as a complication of chronic renal failure. Iatrogenic calcifications are secondary to sucralfate, isotretinoin, or calcium therapy. Dystrophic calcifications occur due to local tissue damage that causes the deposition of calcium salts in fibrotic and inflamed tissue. Patients with GMC can frequently be asymptomatic and the diagnosis is usually made postmortem. Histological findings of GMC include basophilic intraepithelial deposits of calcium within the squamous mucosa which will stain positive on a von Kossa stain. Treatment options for this disease are limited. IV sodium thiosulfate has been described as a potential therapy by competitively binding calcium to form a highly soluble calcium salt. As the prevalence of patients with ESRD increases, clinicians should be mindful of this rare complication and its role as a possible cause for chronic abdominal dyspepsia.

A 34-year-old male presented with multiple gunshot wounds with a bullet lodged in the pelvis next to the rectum. A barium enema demonstrated a leak. Gastroenterology was consulted for bullet retrieval for ballistics and closure of the defect. We describe the techniques utilized to remove the extraluminal bullet and close the defect.