Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

INTRODUCTION: Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. METHODS: We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. RESULTS: The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). CONCLUSION: A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

Kimura-Takemoto Classification: A Tool to Predict Gastric Intestinal Metaplasia Progression to Advanced Gastric Neoplasia.

BACKGROUND AND AIMS: Gastric cancer is a leading cause of morbidity and mortality worldwide. Gastric intestinal metaplasia (GIM) has been described as a key histologic step in the development of gastric adenocarcinoma. However, not all people with GIM develop malignancy. We studied the factors associated with progression to dysplasia and advanced gastric neoplasia (aGN) in patients with baseline GIM. METHODS: Retrospective cohort analysis of patients with baseline GIM and subsequent endoscopic evaluation at Cleveland Clinic Florida and Ohio Main Campus between 2005 and 2017. Demographic and exposure risk factors, as well as Kimura-Takemoto classification (KTc), were used as variables for hazards ratio (HR) and Kaplan-Meier survival-free analysis for aGN and any form of dysplasia progression. RESULTS: There were 708 patients identified with GIM; 29 patients (4.1%) progressed to any degree of dysplasia. From these, LGD was present in 12 cases (1.7%), HGD in 4 cases (0.6%), and gastric cancer in 13 cases (1.8%), for a total of 17 aGN cases. KTc was associated with dysplasia and aGN progression (p < 0.001), and no cases progressed if KTc findings were absent. Open-type KTc was associated with aGN (HR 6.36, p < 0.001) and any dysplasia progression (HR 13.34, p < 0.001) compared to closed-type or absent KTc features. No other factors were associated with aGN or dysplasia progression. Open-type KTc was also associated with shorter cancer survival-free progression. CONCLUSION: Patients with baseline GIM present a higher progression risk to aGN, dysplasia, or cancer if concomitant KTc findings are present, particularly an open-type KTc pattern.

Anti-inflammatory Properties of the Alpha-Melanocyte-Stimulating Hormone in Models of Granulomatous Inflammation.

PURPOSE: Alpha-melanocyte stimulating hormone (α-MSH) is known to have anti-inflammatory effects. However, the anti-inflammatory properties of α-MSH on normal bronchial epithelial cells are largely unknown, especially in the context of in vitro sarcoidosis models. METHODS: We evaluated the anti-inflammatory effects of α-MSH on two different in vitro sarcoidosis models (lung-on-membrane model; LOMM and three-dimensional biochip pulmonary sarcoidosis model; 3D-BSGM) generated from NBECs and an in vivo sarcoidosis mouse model. RESULTS: Treatment with α-MSH decreased inflammatory cytokine levels and downregulated type I interferon pathway genes and related proteins in LOMM and 3D-BSGM models. Treatment with α-MSH also significantly decreased macrophages and cytotoxic T-cells counts in a sarcoidosis mice model. CONCLUSION: Our results confirm the direct role of type I IFNs in the pathogenesis of sarcoid lung granulomas and highlight α-MSH as a potential novel therapeutic agent for treating pulmonary sarcoidosis.

Impact of margin status on outcomes after endoscopic resection of well-differentiated duodenal neuroendocrine tumors.

BACKGROUND AND AIMS: Duodenal neuroendocrine tumors (DNETs) are known to have low metastatic potential and follow an indolent course. Although DNETs <1 cm in size are amenable to endoscopic resection, little is known about the long-term outcomes and recurrence rates of this approach. METHODS: Sixty-three patients with DNETs from 3 centers were retrospectively studied from 2003 to 2018. We analyzed their resection modality (EMR, snare polypectomy, or forceps polypectomy), margin status, risk factors for recurrence, recurrence rate, and endoscopic surveillance patterns. RESULTS: Of the 63 patients who underwent endoscopic resection, 13 (20.6%) had recurrence. The presence of R1 margins was found to be a statistically significant risk factor for recurrence (P = .048). Mean surveillance time for all DNETs was 2.8 ± 2.6 years. Ninety-two percent of recurrences were detected within 3 years of resection. CONCLUSIONS: Our data suggest that the main predictor of recurrence in low-grade DNETs <1.0 cm is the presence of positive tumor margins at the initial endoscopic resection. More frequent, earlier surveillance after resection than that currently recommended by European Neuroendocrine Tumor Society guidelines may be warranted to promptly capture DNET recurrences. Additionally, no recurrences occurred in our cohort after 4 years of surveillance.

Fibrosing cholestatic hepatitis after kidney transplantation from HCV-viremic donors to HCV-negative recipients: A unique complication in the DAA era.

Fibrosing cholestatic hepatitis (FCH) posttransplantation can lead to graft failure and death. In the era of direct acting antiviral therapy (DAA), several studies have demonstrated the efficacy and safety of transplanting hepatitis C virus (HCV)-positive allografts into HCV-negative recipients. In this case series, we present two cases of HCV-negative recipients who underwent kidney transplantation from viremic donors and developed FCH. Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100 000 000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs. One patient has undetectable HCV 12 weeks after completing treatment and the other patient has undetectable HCV after completing DAA treatment. The introduction of DAAs has changed the landscape of solid organ transplantation with the potential to expand the donor pool and increase access to organs. While HCV viremic organs have tremendous potential to increase access to a scarce resource, FCH is a potentially fatal complication and therefore clinicians must maintain a high index of suspicion for this unique complication.

An Extradigital Glomus Tumor of the Median Antebrachial Vein.

Glomus tumors are benign vascular neoplasms that arise from specialized dermal arteriovenous anastomoses called glomus bodies. These tumors are most often found in the digital pulp and subungual region of the fingertips; however, a review of the literature suggests that extradigital glomus tumors may occur more often than is generally recognized. Although most extradigital glomus tumors arise within subcutaneous tissues, glomus tumors have occasionally been found within bones, nerves, and blood vessels. An intravascular glomus tumor of the forearm is a very rare occurrence and only a few cases have been reported in the literature. Here we describe a 55-year-old right-handed man with a 10-year history of exquisite tenderness and dysesthesia of his right proximal forearm. Surgical exploration revealed the presence of a mass arising from the median antebrachial vein, which was confirmed histologically to be a glomus tumor.

Judging pathological assessment in cancer specimens.

The pathologist plays a critical role in the multidisciplinary team in charge of treating cancer patients, as many of the therapeutic decisions rely on the information conveyed through the pathology reports. The task of the pathologist includes not only an accurate assessment of pathological T and N categories, but also the evaluation of other indicators of prognosis including quality of surgery, margins of resection, as well as additional histopathological and molecular markers that influence prognosis and could predict response to therapy.

Depth of injury caused by liquid nitrogen cryospray: study of human patients undergoing planned esophagectomy.

BACKGROUND: Cryotherapy using liquid nitrogen delivered endoscopically has been used for mucosal ablation of esophageal neoplasia. There are no data for the human esophagus on the depth of injury and effects of this technique. AIM: Prospective study to examine the effect of treatment and depth of injury to the human esophagus of liquid nitrogen spray cryotherapy for subjects with esophageal neoplasia before planned esophagectomy. METHODS: Liquid nitrogen spray cryoablation was performed seven days before scheduled esophagectomy for seven males with esophageal carcinoma. Subjects were assigned to either treatment of four cycles of 10 s each (group 1) or two cycles of 20 s each (group 2) applied to a 2-cm segment of healthy esophagus above the tumor area. Main outcomes measured were: mean depth of injury (mm); surface displaying mucosal ablation, and adverse events. RESULTS: Mucosal destruction was similar for both groups (group 1, 95%; group 2, 93%; p = NS). Deeper injury was observed for group 2; mean depth was 5.4 mm compared with 4.0 mm for group 1. Cryonecrosis reached the submucosa for 60% (12/20) of subjects in group 1 versus 93% (14/15) of subjects in group 2 (p = 0.04, two-tailed Fisher's exact test). No serious adverse events occurred. No perforation was seen in the resected esophagus. CONCLUSION: Mucosal ablation with liquid nitrogen spray cryotherapy was highly effective in inducing mucosal necrosis; the doses assessed had similar effects. Ablation reached the submucosa more often with longer spray time despite fewer treatment cycles.

DICER1-related Sertoli-Leydig cell tumor and rhabdomyosarcoma: An evolving disease with a challenging clinical course and treatment: A case report.

DICER1 syndrome is a rare genetic disorder predisposing young patients to multiple types of cancer. A 17-year-old woman with a history of mixed Sertoli-Leydig cell tumor and juvenile granulosa cell tumor of the left ovary at age 14 presented with a pelvic mass. She underwent fertility preservation cytoreductive surgery and the pathology showed high-grade sarcoma with rhabdomyosarcomatous differentiation. After the surgery, patient received one cycle of chemotherapy but her disease continued to progress. She therefore underwent total hysterectomy, right salpingo-oophorectomy and hyperthermic intraperitoneal chemotherapy followed by consolidation chemotherapy. Magnetic resonance imaging revealed no evidence of the disease before and after the completion of her chemotherapy. Genetic testing confirmed the DICER1 pathogenic variant. However, she presented again with a recurrence of the disease 6 months later and ultimately died of the disease 11 months after the surgery. Our case demonstrates the challenging management of this rare disease in a young patient and the need for new and effective treatments.

Colorectal Carcinoma With Sarcomatoid Components: Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

Primary biliary cirrhosis is more severe in overweight patients.

GOALS: We sought to determine whether features of metabolic syndrome (MS) and histologic features of nonalcoholic steatohepatitis (NASH) are associated with increased fibrosis in patients with primary biliary cirrhosis (PBC). BACKGROUNDS: PBC is a chronic, progressive cholestatic disease. MS is strongly associated with NASH and fibrosis progression in some liver diseases. STUDY: Patients with PBC seen consecutively at the University of Miami between 1985 and 2008 who had antimitochondrial antibody positivity and a liver biopsy performed at this center at the time of diagnosis were identified. Demographics, clinical features, and biochemical parameters were collected. All liver biopsies were reviewed by a single blinded pathologist for features of NASH, PBC, and fibrosis. The impact of NASH and features of MS on liver biopsy findings were analyzed. RESULTS: Forty-nine patients [median age 51 (34 to 78) years, 98% females] were enrolled. Higher degree of steatosis, severe inflammatory grade, and severe biliary duct damage were each associated with advanced fibrosis (P<0.0001). Regarding MS, only overweight status [body mass index (BMI) ≥ 25] was associated with nonalcoholic fatty liver activity score (NAS) ≥ 5 (P<0.0001), biliary duct damage (P<0.0001), and advanced fibrosis (71% vs. 32%, P=0.007). Patients with NAS ≥ 5 had more severe fibrosis (14/15, 96% vs. 11/34, 44%; P=0.0001) and more severe biliary duct damage (13/15, 87% vs. 3/34, 9%; P=<0.0001). CONCLUSIONS: NASH and BMI ≥ 25 are associated with severe biliary duct damage and fibrosis in patients with PBC. BMI could become a useful noninvasive tool to predict advanced fibrosis in PBC.

Primary adenocarcinoma of the thymus: an immunohistochemical and molecular study with review of the literature.

BACKGROUND: Primary adenocarcinoma of thymus is extremely rare. CASE PRESENTATION: This is a case of primary adenocarcinoma with intestinal differentiation and focal mucin production in the thymus. Thymic cyst was associated with this tumor. Intestinal differentiation was confirmed by immunohistochemical stain with positivity for CDX-2, CK20, villin, MOC31 and focal positivity of CK7. Array comperative genomic hybridization (CGH) analysis showed a complex pattern of chromosomal imbalances including homozygous deletion at the HLA locus in chromosomal region 6p21.32. CONCLUSION: This rare tumor shows a similar genetic aberration with other studied thymic epithelial tumors.

Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma.

INTRODUCTION: GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients. METHODS: Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis. RESULTS: GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments. CONCLUSIONS: The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.

Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy.

BACKGROUND: Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies. AIM: To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients. METHODS: We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA. RESULTS: Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection. CONCLUSION: After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.

Potential clinical complications of Orise™ gel use, a new submucosal lifting agent: experience from a tertiary care center and review of the literature.

Background: Endoscopic mucosal resection (EMR) involves forming a fluid cushion in the submucosal area with a lifting agent, followed by superficial resection. Orise™ gel is one of the commonly used lifting agents for EMR. We present a case series and literature review that analyzes the characteristic histopathological findings and clinical implications observed where Orise™ gel was used before EMR. Methods: Colon resection specimens and prior EMR specimens where Orise™ gel was used were reviewed for patients undergoing EMR between January 2018 and December 2020. The literature review included relevant studies from the Medline and Cochrane databases from January 2018 to December 2020. Results: A total of 12 colon polyp EMRs using Orise gel were performed during the study period. Seven patients (58.34%) underwent surgical resection. Histological examination revealed that, after the EMR procedure, the Orise™ gel material changed its morphological characteristics over time from a basophilic (bluish) non-inflamed pattern to an eosinophilic (pink) type pattern, eliciting a foreign body reaction. The endoscopic appearance and examination of the excised specimens weeks after injection gave the impression of a mass in some cases. The material was also present transmurally and in some cases in the peri-intestinal adipose tissue. Conclusions: It was observed that Orise™ gel use elicits a foreign body-type granulomatous reaction. This potential side effect may lead to overdiagnosis of a mass/lesion and unnecessary surgical interventions. This case series and review of the literature aims to increase awareness of the changes caused by Orise™ gel in the gastrointestinal tract.

Medullary carcinoma of the colon: A comprehensive analysis of the National Cancer Database.

PURPOSE: Medullary carcinomas (MC) of the colon are uncommon tumors. In this study, we analyzed demographic and disease characteristics as well as survival outcomes of MC versus undifferentiated (UDA) and poorly differentiated (PDA) adenocarcinomas (AC) of the colon. MATERIALS AND METHODS: The National Cancer Database (2004-2018) was utilized to identify patients with colon cancer. Patient demographics (including age, gender, race), disease characteristics (including grade, TNM stage, carcinoembryonic levels, perineural and lymphovascular invasion, lymph node status, microsatellite stability, KRAS mutation, and primary tumor site), and facility type and location were evaluated. Chi-square tests were used to compare descriptive data. Cox Regression and Kaplan Meier analyses were used to analyze survival characteristics. RESULTS: 1,041,753 patients with colon cancer were identified of whom 2709 patients had MC and 897,902 had AC (136,597 PDA and 18,042 UDA). MC was seen in older patients (mean age 74 ± 13 years) and women (72.5% vs. 27.5% males). Most MCs were poorly differentiated (63.3%), and 82.4% of patients with MC had microsatellite instability. Fewer patients with MC had perineural invasion (15.6% vs. 22.0% in PDA and 22.4% in UDA, p < 0.001) and positive lymph nodes (38.4% versus 59.9% with PDA and 59.7% with UDA, p < 0.0001). MC diagnosis increased by year (Cochran-Armitage trend test, p < 0.0001). Kaplan Meir analysis revealed a better prognosis for patients with MC when compared to PDA or UDA (p < 0.001). CONCLUSION: Given the rarity, pathologists should maintain a high suspicion for MC when encountering poorly differentiated or undifferentiated right-sided colon cancer with associated MSI-H.

A case of cardiac sarcoidosis with successful heart transplantation after COVID-19 infection.

Arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis can both present with ventricular tachycardia. We report a case of a patient whose histological diagnosis was not only confirmed by the transplanted heart but who also underwent successful transplantation after overcoming COVID-19. .

Autoimmune Hepatitis With Concomitant Pernicious Anemia: A Rare Association.

The co-occurrence of autoimmune hepatitis (AIH) and pernicious anemia (PA) is extremely rare. We present a case of a 70-year-old woman with AIH who presented for the evaluation of poor appetite and weight loss. Laboratory studies were significant for microcytic anemia, B12, and iron deficiency. Esophagogastroduodenoscopy showed diffuse gastric mucosal atrophy, and the pathology from the body of the stomach showed chronic gastritis. Additional testing was positive for parietal cell antibody and intrinsic factor blocking antibody, confirming the diagnosis of PA. To the best of our knowledge, there is only one documented case of AIH associated with PA.

Unique Case of a Hamartomatous Duodenal Polyp Associated With Intestinal Schistosomiasis.

Schistosomiasis is a trematode infection rarely diagnosed in the United States. Intestinal involvement is common with chronic infection and causes abdominal pain, changes in bowel habits, hematochezia, and polyp formation. Chronic, disseminated infection can affect the intestines causing the aforementioned symptoms, but reports of intestinal polyps are rare. Most cases are inflammatory fibrous polyps in the colon. There are very few cases reported in the literature of hamartomatous polyps arising in the small intestine. We present the rare case of a U.S.-born, 35-year-old woman diagnosed with a large duodenal hamartomatous polyp in the setting of intestinal schistosomiasis.

A Rare Case of Metastatic Colon Cancer in a Patient With Squamous Cell Carcinoma of the Tongue.

Squamous cell carcinoma (SCC) of the colon, both primary and metastatic, are extremely rare malignancies. We present a case of a 60-year-old man with metastatic SCC of the tongue status after radiation and chemotherapy who presented with fatigue and melena. Colonoscopy revealed a 5 cm mass in the transverse colon. Pathology established the diagnosis of poorly differentiated SCC with p16 immunostaining, similar to biopsies from his initially diagnosed lingual cancer. To the best of our knowledge, there are no previously reported cases of primary SCC of the tongue metastasizing to the colon.