Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report.

INTRODUCTION: We evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC. METHODS: Retrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022. RESULTS: Thirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27-123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients. Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4-542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31-90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively. CONCLUSION: One-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

The Characteristics of Isolated Bulb Celiac Disease in Children.

OBJECTIVES: Mucosal injury in celiac disease (CD) patients can be patchy, and up to 12% of CD patients can have mucosal changes limited to the duodenal bulb. Hence, recent guidelines recommend obtaining bulb biopsies in addition to distal duodenum. This study aimed to describe a cohort of children with isolated bulb CD and assess the benefit of separating bulb biopsies. METHODS: A retrospective chart review between January 2011 and January 2022 at 2 medical centers was conducted. We included children with CD who underwent endoscopy with separated biopsies from the bulb and distal duodenum. A blinded pathologist performed Marsh-Oberhuber grading on selected cases. RESULTS: We identified 224 CD patients, of which 33 (15%) had histologically confirmed isolated bulb CD. Patients with isolated bulb CD were older at diagnosis (10 vs 8 years; P = 0.03). Median anti-tissue transglutaminase immunoglobulin A (TTG IgA) level was lower in isolate bulb CD (2.8 vs 16.7 times the upper limit of normal [ULN], P < 0.001). Almost 88% (29/33) of isolated bulb CD patients had an anti-TTG IgA value of less than 10 times the ULN. Time to anti-TTG IgA normalization (mean 14 months) was similar between the 2 groups. A pathologist review of diagnostic biopsies could not distinguish between the bulb and distal duodenum biopsies in approximately one-third of the reviewed samples. CONCLUSIONS: Separating bulb from distal duodenum biopsies can be considered during CD diagnosis, particularly in children with anti-TTG IgA levels less than 10 times the ULN. Larger prospective cohorts are needed to decide whether isolated bulb CD is a unique cohort or an early stage of the conventional CD.

PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68 Ga-PSMA-11 PET Using Cyclotron-Produced 68 Ga.

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10-5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10-6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism.

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

Carboxypeptidase A1 and regenerating islet-derived 1α as new markers for pancreatic acinar cell carcinoma.

Acinar cell carcinoma (ACC) is a rare tumor that differentiates toward pancreatic acinar cells and shows evidence of pancreatic enzyme production. Mixed acinar-neuroendocrine carcinoma (MANC) is defined as having more than 30% of both acinar and neuroendocrine cell types as per immunohistochemistry analysis. Trypsin is currently the most commonly used stain for acinar differentiation. In this study, we investigate the utility of two novel markers, carboxypeptidase A1 (CPA1) and regenerating islet-derived 1α (REG1a), in diagnosing ACC/MANC. Immunohistochemical staining for CPA1 and REG1a was performed on 14 cases of ACC and 5 cases of MANC as well as on 80 other pancreatic tumors including 20 cases each of ductal adenocarcinoma, well-differentiated neuroendocrine tumor, mucinous cystic neoplasm, and solid pseudopapillary tumor. All ACCs and MANCs were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, and 3 focal). A diffuse or patchy staining pattern was significantly more common in ACC/MANC cases (100% diffuse/patchy for CPA1 and 84% for REG1a) than in other pancreatic tumors (5% diffuse/patchy for CPA1 and 7.5% for REG1a), with a P-value of <0.0001 for both CPA1 and REG1a. The sensitivity and specificity of diffuse/patchy staining for CPA1 and REG1a in diagnosing pancreatic ACC/MANC were 100% and 95% for CPA1 and 84% and 93% for REG1a, respectively. In conclusion, CPA1 and REG1a are sensitive markers for ACC that can be used as additional acinar cell differentiation markers to help in the diagnosis of pancreatic ACC and MANC. A negative result for CPA1 virtually excludes ACC/MANC.

Dichotomous regulation of group 3 innate lymphoid cells by nongastric Helicobacter species.

Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius, isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt+ group 3 ILCs (ILC3s), especially T-bet+ ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host-microbe interactions that critically sustain the maintenance of intestinal ILC3s.

Bi-lobar liver biopsy via EUS enhances the assessment of disease severity in patients with non-alcoholic steatohepatitis.

BACKGROUND: In patients with non-alcoholic fatty liver disease (NAFLD), all-cause mortality increases with fibrosis stage. Liver biopsy (LB), performed predominantly in the right lobe, assesses fibrosis, however, right lobe LB may not be sufficient due to histological variation in different lobes. Endoscopic ultrasound (EUS) allows for biopsy of right and left liver lobes in the same setting. METHODS: This retrospective study assessed for histologic variability amongst left and right liver lobe (L:R) specimens obtained via EUS at a tertiary care center. Between January 2012 and December 2015, 38 NAFLD patients underwent LB, in whom both lobes were sampled. RESULTS: L:R agreement was near-perfect for steatosis (κ = 0.816, 95% CI 0.674, 0.958), good for ballooning (κ = 0.740, 95% CI 0.565, 0.916) and moderate for lobular inflammation (κ = 0.401 95% CI 0.110, 0.692) and fibrosis (κ = 0.473, 95% CI 0.275, 0.672). Intra-observer variability assessed by blinded repeat slide readings was almost perfect for fibrosis and steatosis (κ = 1, 95% CI 1, 1 and κ = 0.939, 95% CI 0.881, 0.997 respectively) and substantial for lobular inflammation (κ = 0.725, 95% CI 0.584, 0.866). Only right lobe assessment underestimated fibrosis in 21%, inflammation in 13%, and steatosis and ballooning in 8% cases. CONCLUSIONS: These data indicate that in NAFLD, due to regional variation, EUS-guided bi-lobar LB improves assessment of disease activity and fibrosis.

Endoscopic ultrasound-guided biopsy in chronic liver disease: a randomized comparison of 19-G FNA and 22-G FNB needles.

Background and study aims Endoscopic ultrasound-guided liver biopsy uses a 19-gauge (G) needle for parenchymal liver biopsies. We evaluated tissue yields with a 22G fine-needle biopsy (FNB) versus 19G FNA fine-needle aspirate (FNA) device. Patients and methods Biopsies were obtained from 20 patients using the 19G FNA and 22G FNB randomizing each in a cross-over fashion with a blinded outcome assessor. Tissue adequacy for histologic evaluation was the primary outcome, or the proportion of specimens obtaining pathologic diagnosis (portal structures ≥ 5 or length of the longest piece ≥ 15 mm). Additional secondary outcomes included portal and centrilobular inflammation/fibrosis, length of the longest piece, aggregate specimen length, and small (< 5 mm), medium (5 - 8 mm) and large (> 8 mm) fragments. Results were compared in a per needle basis. Patients with cirrhosis were excluded. Results Eighty biopsies (40 each 19G FNA and 22G FNB) were obtained. Tissue adequacy was greater for the 19G FNA (88 %) versus 22G FNB (68 %), ( P  = 0.03). There was no difference in total portal structures for the 19G FNA (7.4) and 22G FNB (6.1), ( P  = 0.28). There was no difference in pre-processing outcomes. After processing, length of the longest piece was higher for the 19G FNA (9.1 mm) versus 22G FNB (6.6 mm), ( P  = 0.02). More total post-processing small fragments 29.9 versus 20.7, ( P  = 0.01) and fewer large fragments 1.0 versus 0.4 for the 22G FNB ( P  = 0.01) were detected. Conclusions Tissue adequacy was higher for the 19G FNA versus 22G FNB needle. The 22G FNB needle produced samples more prone to fragmentation during specimen processing.

A prospective pilot comparison of wet and dry heparinized suction for EUS-guided liver biopsy (with videos).

BACKGROUND AND AIMS: As EUS-guided liver biopsy sampling (EUS-LB) becomes more widely used, further studies have investigated ways to improve tissue yields. Use of a heparin-primed needle may lead to less clotting of blood within the needle, improve tissue recovery, and decrease fragmentation. The purpose of this study was to prospectively evaluate wet suction using a heparin-primed needle for EUS-LB. METHODS: This was a prospective crossover study evaluating wet suction for EUS-LB in parenchymal liver disease. The primary outcome was specimen adequacy, defined by an aggregate specimen length ≥15 mm and ≥5 complete portal tracts (CPTs). Secondary outcomes included number of CPTs, length of the longest piece, aggregate specimen length, and number of small (≤4 mm), medium (5-8 mm), and large (≥9 mm) fragments. Adverse events were tracked at 7 and 30 days. RESULTS: One hundred twenty biopsy specimens were collected from 40 participants (3 specimens per patient). Specimen adequacy occurred in 39 wet heparin (98%), 37 dry heparin (93%), and 30 dry needle biopsy samples (80%; 95% confidence interval [CI], .14-.18; P = .01). There was no difference between dry needle techniques. Length of the longest piece was 8.9 mm for wet heparin and 5.8 mm for dry techniques (95% CI, .33-1.53; P = .003). Aggregate specimen length was 49.2 mm for wet heparin and 23.9 mm for dry heparin (95% CI, -46.34 to 44.94; P = .003). Mean CPT count was 7.0 for wet heparin versus 4.0 for dry (95% CI, .74-6.26; P = .01). There were more medium (2.0 vs 1.0; 95% CI, .06-1.24; P = .03) and large (1.0 versus 0.0; 95% CI, .33-1.53; P = .003) fragments with wet suction with no difference in small fragments between groups. CONCLUSIONS: The use of wet suction EUS-LB demonstrated improved tissue adequacy compared with dry needle techniques. (Clinical trial registration number: NCT03103997.).

Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants.

PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient-participants and their clinicians. We queried patient-participants' electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient-participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient-participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer-including a stage 1C fallopian tube cancer-via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

The Aryl Hydrocarbon Receptor Preferentially Marks and Promotes Gut Regulatory T Cells.

The local environment may affect the development and function of tissue-resident T regulatory cells (Tregs), which are crucial for controlling inflammation. Although the aryl hydrocarbon receptor (Ahr), an environmental sensor, is expressed by Tregs, its role in Treg cell development and/or function remains elusive. Here, we generated mouse genetic models to ablate or activate Ahr expression specifically in Tregs. We showed that Ahr was expressed more abundantly by peripherally induced Tregs (pTregs) in the gut and that its expression was independent of microbiota. Ahr was important for Treg gut homing and function. Ahr inhibited pro-inflammatory cytokines produced by Tregs but was dispensable for Treg stability. Furthermore, Ahr-expressing Tregs had enhanced in vivo suppressive activity compared with Tregs lacking Ahr expression in a T cell transfer model of colitis. Our data suggest that Ahr signaling in Tregs may be important for gut immune homeostasis.

Case report of gastric outlet obstruction from metastatic lobular breast carcinoma.

BACKGROUND: The most common malignancy to cause gastric outlet obstruction is primary gastric adenocarcinoma and it is followed by carcinoma of the pancreas and gallbladder. Herein, we report a case of gastric outlet obstruction secondary to metastatic lobular breast carcinoma. CASE PRESENTATION: Fifty-seven year old Caucasian female with recently diagnosed metastatic lobular breast carcinoma to skin was referred to gastroenterology for evaluation of dyspepsia and dysphagia. She has past medical history significant for acid reflux and Clostridium difficile colitis. Computed tomography of her abdomen showed diffused bowel wall thickening without evidence of bowel obstruction. Due to persistent abdominal pain, an upper endoscopy was performed. The upper endoscopy showed gastritis and gastric stenosis in the gastric antrum. These lesions were biopsied and dilated with a balloon dilator. The biopsy of the gastric antrum later showed a metastatic carcinoma of breast origin with typical tumor morphology and immune-phenotype. CONCLUSIONS: Differentiating metastatic breast carcinoma from primary gastric adenocarcinoma cannot be done using histological examination alone. Immunohistochemistry is needed to differentiate the two based on staining for estrogen and progesterone receptors. The presence of gross cystic disease fluid protein 15 is also suggestive of metastatic breast carcinoma. The stomach has a significant capacity to distend (up to 2-4 L of food) and malignant gastric outlet obstruction is often undetected clinically until a high-grade obstruction develops. Our case demonstrates valuable teaching point in terms of broadening our differentials for gastric outlet obstruction. When patients present with gastric outlet obstruction, both non-malignant and malignant causes of gastric outlet obstruction should be considered. Once adenocarcinoma has been determined to be the cause of gastric outlet obstruction, further immunohistochemistry is needed to differentiate breast carcinoma from other carcinomas.

Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros.

Proper immune responses are needed to control pathogen infection at mucosal surfaces. IL-22-producing CD4(+) T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. In this study, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22-producing, but not IL-17-producing, CD4(+) T cells in the gut. Adoptive transfer of CD4(+) T cells from these Ikaros-mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived regulatory T cell (Treg) compartment in these Ikaros-mutant mice, TGF-ß, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros-mutant CD4(+) T cells in vitro and, instead, promoted IL-22. Aberrant upregulation of IL-21 in CD4(+) T cells expressing mutant Ikaros was responsible, at least in part, for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor, but not RORγt, was required for aberrant IL-22 expression by Ikaros-mutant CD4(+) T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data identified new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4(+) T cells.

PIK3CA mutations in mucinous cystic neoplasms of the pancreas.

OBJECTIVES: Mucinous cystic neoplasms (MCNs) are rare, potentially curable, mucin-producing neoplasms of the pancreas. We have previously reported PIK3CA (phosphoinositide-3-kinase catalytic subunit, p110α) mutations in intraductal papillary mucinous neoplasms, another mucin-producing neoplasm of the pancreas. In this study, we analyzed the presence of PIK3CA and AKT1/PKB (V-akt murine thymoma viral oncogene homolog 1) hot-spot mutations in MCN specimens. METHODS: Using the genomic DNA sequencing of tumor tissues isolated by laser capture microdissection, we evaluated 15 well-characterized MCNs for the E542K, E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and the E17K mutation in the AKT1 gene. RESULTS: A hot-spot mutation (E545K) of the PIK3CA gene was detected in 1 of the 15 MCNs and further confirmed by a mutant-enriched method. Interestingly, this mutation was found to be present only in the high-grade but not in low-grade dysplastic epithelium obtained from this neoplasm and coexisted with a KRAS mutation. No mutations were identified in the AKT1 gene. CONCLUSIONS: Our data, when combined with previous reports on intraductal papillary mucinous neoplasms, indicate that oncogenic activation of the PI3K pathway involving PIK3CA gene mutations can contribute to the progression of mucin-producing neoplasms but not pancreatic intraepithelial neoplasia. PIK3CA status could be useful for understanding their progression to malignancy.

Immunohistochemical stains of proliferating cell nuclear antigen, insulin-like growth factor 2 and clusterin help distinguish malignant from benign liver nodular lesions.

AIMS: To explore the immunohistochemical utility of proliferating cell nuclear antigen (PCNA), insulin-like growth factor 2 (IGF2) and clusterin in the distinction between malignant and benign liver nodular lesions. METHODS: Immunohistochemical stains for PCNA, IGF2 and clusterin were performed on 284 liver nodular lesions, including 33 hepatocellular adenomas (HCA), 40 focal nodular hyperplasias (FNH), 77 large regenerative nodules (LRN) and 134 hepatocellular carcinomas (HCC). RESULTS: Strong and diffuse nuclear PCNA immunoreactivity was observed in 103 (77%) HCCs but in only 2 (6%) HCAs. None of the FNH and LRN cases showed a strong and diffuse staining pattern. All HCAs, 95% of FNHs and 92% of LRNs showed cytoplasmic IGF2 expression, with a strong staining observed in 70% of HCAs, 20% of FNHs and 30% of LRNs. This was in marked contrast to that observed in HCCs, where 66% of HCCs demonstrated a weak and focal/patchy immunostaining pattern and another 25% showed no detectable IGF2 immunoreactivity. In comparison with their adjacent non-lesional hepatocytes, 75% of HCCs showed decreased IGF2 expression. However, decreased IGF2 expression was not evident in HCAs, FNHs and LRNs. Cytoplasmic staining for clusterin was seen in both benign and malignant nodular lesions. However, an enhanced and exaggerated pericanalicular staining pattern was observed in 75% of HCCs, which was not demonstrated in HCAs, FNHs and LRNs. CONCLUSIONS: PCNA, IGF2 and clusterin show unique immunostaining characteristics in HCCs, which can be useful adjuncts to other currently available markers to aid in the distinction of HCC from benign liver nodular lesions.

Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora.

Aryl hydrocarbon receptor (Ahr) is crucial for the maintenance and function of group 3 innate lymphoid cells (ILCs), which are important in gut immunity. Because Ahr promotes T helper 17 (Th17) cell differentiation in vitro, it is reasonable to expect that Ahr would enhance Th17 cells in vivo. Instead, we show that Ahr deficiency caused increased intestinal Th17 cells, raising the possibility that group 3 ILCs could negatively regulate Th17 cells. Reduced innate interleukin-22 (IL-22) in Ahr-deficient mice allowed expansion of commensal segmented filamentous bacteria (SFB), known to promote Th17 cells. Compared to Rorc(+/+)Ahr(-/-) mice, Rorc(gfp/+)Ahr(-/-) mice had further reduced group 3 ILCs and were prone to spontaneous colitis with increased SFB and Th17 cells. Innate expression of Ahr played a protective role in T-cell-mediated experimental colitis by suppressing pathogenic Th17 cells. Our data reveal an intricate balance between ILCs and Th17 cells regulated by Ahr and commensal flora.

The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

Innate lymphoid cells (ILCs) expressing the nuclear receptor RORγt are essential for gut immunity presumably through production of interleukin-22 (IL-22). The molecular mechanism underlying the development of RORγt(+) ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in RORγt(+) ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal RORγt(+) ILCs. Without Ahr, RORγt(+) ILCs had increased apoptosis and less production of IL-22. RORγt interacted with Ahr and promoted Ahr binding at the Il22 locus. Upon IL-23 stimulation, Ahr-deficient RORγt(+) ILCs had reduced IL-22 expression, consistent with downregulation of IL-23R in those cells. Ahr-deficient mice succumbed to Citrobacter rodentium infection, whereas ectopic expression of IL-22 protected animals from early mortality. Our data uncover a previously unrecognized physiological role for Ahr in promoting innate gut immunity by regulating RORγt(+) ILCs.

Iron deposition surrounding the hepatic veins of cirrhotic patients on MRI.

PURPOSE: To provide the first description of a pattern of iron deposition surrounding the hepatic veins in patients with alcoholic cirrhosis and postulate the reason for these findings. MATERIALS AND METHODS: Two institutions' teaching files were searched for abdominal MRI studies between January 2003 and April 2009 which showed iron deposition within the liver surrounding the hepatic veins. MRI exams were reviewed by two radiologists for iron deposition and signs of portal hypertension. Liver explant pathology reports were also reviewed. RESULTS: Four patients with alcoholic cirrhosis demonstrated perihepatic vein low signal intensity on T1 gradient echo images correlating with iron overload confirmed at histopathologic evaluation of explanted livers. CONCLUSION: This is the first described uncommon distribution of iron deposition surrounding the hepatic veins. This pattern is well seen on in-phase T1 gradient echo sequences because of the T2* effects in this sequence.

A unique pathology associated with pelvic pain and adnexal mass.

OBJECTIVE: To present a unique case of pelvic pain. DESIGN: Case report. SETTING: Academic institution. PATIENT(S): Thirty-nine year-old with history of endometriosis presented with pelvic pain and possible adnexal mass. INTERVENTION(S): Imaging results were not consistent and suggested possible adnexal mass and hydrosalpinx in different studies. Physical exam was concerning for a vaginal mass that was felt not to be contiguous with the adnexa. At laparoscopy, a 3 cm pararectal mass was identified immediately lateral to the uterosacral ligament and medial to the ureter. This mass was completely resected laparoscopically. MAIN OUTCOME MEASURE(S): Resolution of pelvic pain. RESULT(S): Pathologic diagnosis was ganglioneuroma. Postoperatively, the patient had resolution of her pelvic pain. CONCLUSION(S): Pelvic ganglioneuromas are a very rare entity but emphasize the importance of a broad differential for pelvic pain.